research articles on molecular biology

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PSMD1 and PSMD2 regulate HepG2 cell proliferation and apoptosis via modulating cellular lipid droplet metabolism

Obesity and nonalcoholic steatohepatitis (NASH) are well-known risk factors of hepatocellular carcinoma (HCC). The lipid-rich environment enhances the proliferation and metastasis abilities of tumor cells. Pre...

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The effect of BACE1-AS on β-amyloid generation by regulating BACE1 mRNA expression

The BACE1 antisense transcript (BACE1-AS) is a conserved long noncoding RNA (lncRNA). The level of BACE1-AS is significantly increased and the level of the BACE1 mRNA is slightly increased in subjects with AD....

Overlapping transcriptional expression response of wheat zinc-induced facilitator-like transporters emphasize important role during Fe and Zn stress

Hexaploid wheat is an important cereal crop that has been targeted to enhance grain micronutrient content including zinc (Zn) and iron (Fe). In this direction, modulating the expression of plant transporters i...

MiR-32-5p influences high glucose-induced cardiac fibroblast proliferation and phenotypic alteration by inhibiting DUSP1

The current study aimed to investigate the effects of miR-32-5p on cardiac fibroblasts (CFs) that were induced with high levels of glucose; we also aimed to identify the potential mechanisms involved in the re...

Correction to: A protocol for custom CRISPR Cas9 donor vector construction to truncate genes in mammalian cells using pcDNA3 backbone

The original article [1] contains three erroneous mentions of usage of a restriction enzyme— Bst Z17I—in the Methods section as displayed in the following sentences.

The original article was published in BMC Molecular Biology 2018 19 :3

Comparison of miRNA - 101a - 3p and miRNA - 144a - 3p regulation with the key genes of alpaca melanocyte pigmentation

Many miRNA functions have been revealed to date. Single miRNAs can participate in life processes by regulating more than one target gene, and more than one miRNA can also simultaneously act on one target mRNA....

Correction to: MicroRNA-325-3p protects the heart after myocardial infarction by inhibiting RIPK3 and programmed necrosis in mice

The original article [1] contains an error whereby Fig. 7 displays incorrect results; the correct version of Fig. 7 can be viewed ahead in this Correction article and should be considered in place of the origi...

The original article was published in BMC Molecular Biology 2019 20 :17

MicroRNA-325-3p protects the heart after myocardial infarction by inhibiting RIPK3 and programmed necrosis in mice

Receptor-interacting serine-threonine kinase 3 (RIPK3)-mediated necroptosis has been implicated in the progression of myocardial infarction (MI), but the underlying mechanisms, particularly whether microRNAs (...

The Correction to this article has been published in BMC Molecular Biology 2019 20 :18

Giant group I intron in a mitochondrial genome is removed by RNA back-splicing

The mitochondrial genomes of mushroom corals (Corallimorpharia) are remarkable for harboring two complex group I introns; ND5-717 and COI-884. How these autocatalytic RNA elements interfere with mitochondrial ...

Exploration of carbohydrate binding behavior and anti-proliferative activities of Arisaema tortuosum lectin

Lectins have come a long way from being identified as proteins that agglutinate cells to promising therapeutic agents in modern medicine. Through their specific binding property, they have proven to be anti-ca...

Characterization of cadmium-responsive MicroRNAs and their target genes in maize ( Zea mays ) roots

Current research has shown that microRNAs (miRNAs) play vital roles in plant response to stress caused by heavy metals such as aluminum, arsenic, cadmium (Cd), and mercury. Cd has become one of the most hazard...

Identification and validation of reference genes for real-time quantitative RT-PCR analysis in jute

With the availability of genome sequences, gene expression analysis of jute has drawn considerable attention for understanding the regulatory mechanisms of fiber development and improving fiber quality. Gene e...

Small nucleolar RNA Sf-15 regulates proliferation and apoptosis of Spodoptera frugiperda Sf9 cells

Small nucleolar RNAs (snoRNAs) function in guiding 2′- O -methylation and pseudouridylation of ribosomal RNAs (rRNAs) and small nuclear RNAs (snRNAs). In recent years, more and more snoRNAs have been found to play ...

Key genes differential expressions and pathway involved in salt and water-deprivation stresses for renal cortex in camel

Camels possess the characteristics of salt- and drought-resistances, due to the long-time adaption to the living environment in desert. The camel resistance research on transcriptome is rare and deficient, esp...

Development of a novel selection/counter-selection system for chromosomal gene integrations and deletions in lactic acid bacteria

The underlying mechanisms by which probiotic lactic acid bacteria (LAB) enhance the health of the consumer have not been fully elucidated. Verification of probiotic modes of action can be achieved by using sin...

Selection of reference genes for the quantitative real-time PCR normalization of gene expression in Isatis indigotica fortune

Isatis indigotica , a traditional Chinese medicine, produces a variety of active ingredients. However, little is known about the key genes and corresponding expression profiling involved in the biosynthesis pathwa...

MEF2A alters the proliferation, inflammation-related gene expression profiles and its silencing induces cellular senescence in human coronary endothelial cells

Myocyte enhancer factor 2A (MEF2A) plays an important role in cell proliferation, differentiation and survival. Functional deletion or mutation in MEF2A predisposes individuals to cardiovascular disease mainly...

Transcriptomic responses to grazing reveal the metabolic pathway leading to the biosynthesis of domoic acid and highlight different defense strategies in diatoms

A major cause of phytoplankton mortality is predation by zooplankton. Strategies to avoid grazers have probably played a major role in the evolution of phytoplankton and impacted bloom dynamics and trophic ene...

RNA sequencing, selection of reference genes and demonstration of feeding RNAi in Thrips tabaci (Lind.) (Thysanoptera: Thripidae)

Thrips tabaci is a severe pest of onion and cotton. Due to lack of information on its genome or transcriptome, not much is known about this insect at the molecular level. To initiate molecular studies in this ins...

A fragment activity assay reveals the key residues of TBC1D15 GTPase-activating protein (GAP) in Chiloscyllium plagiosum

GTPase-activating proteins (GAPs) with a TBC (Tre-2/Bub2/Cdc16) domain architecture serve as negative regulators of Rab GTPases. The related crystal structure has been studied and reported by other members of ...

HexA is required for growth, aflatoxin biosynthesis and virulence in Aspergillus flavus

Woronin bodies are fungal-specific organelles whose formation is derived from peroxisomes. The former are believed to be involved in the regulation of mycotoxins biosynthesis, but not in their damage repair fu...

Genome-wide identification of brain miRNAs in response to high-intensity intermittent swimming training in Rattus norvegicus by deep sequencing

Physical exercise can improve brain function by altering brain gene expression. The expression mechanisms underlying the brain’s response to exercise still remain unknown. miRNAs as vital regulators of gene ex...

Graphene oxide down-regulates genes of the oxidative phosphorylation complexes in a glioblastoma

Recently different forms of nanographene were proposed as the material with high anticancer potential. However, the mechanism of the suppressive activity of the graphene on cancer development remains unclear. ...

MiRNAs differentially expressed in skeletal muscle of animals with divergent estimated breeding values for beef tenderness

MicroRNAs (miRNAs) are small noncoding RNAs of approximately 22 nucleotides, highly conserved among species, which modulate gene expression by cleaving messenger RNA target or inhibiting translation. MiRNAs ar...

The Dictyostelium discoideum homologue of Twinkle, Twm1, is a mitochondrial DNA helicase, an active primase and promotes mitochondrial DNA replication

DNA replication requires contributions from various proteins, such as DNA helicases; in mitochondria Twinkle is important for maintaining and replicating mitochondrial DNA. Twinkle helicases are predicted to a...

Matrix association region/scaffold attachment region (MAR/SAR) sequence: its vital role in mediating chromosome breakages in nasopharyngeal epithelial cells via oxidative stress-induced apoptosis

Oxidative stress is known to be involved in most of the aetiological factors of nasopharyngeal carcinoma (NPC). Cells that are under oxidative stress may undergo apoptosis. We have previously demonstrated that...

Molecular analysis of NPAS3 functional domains and variants

NPAS3 encodes a transcription factor which has been associated with multiple human psychiatric and neurodevelopmental disorders. In mice, deletion of Npas3 was found to cause alterations in neurodevelopment, as w...

Integration of transcriptome and proteome profiles in glioblastoma: looking for the missing link

Glioblastoma (GB) is the most common and aggressive tumor of the brain. Genotype-based approaches and independent analyses of the transcriptome or the proteome have led to progress in understanding the underly...

Analyses of changes in myocardial long non-coding RNA and mRNA profiles after severe hemorrhagic shock and resuscitation via RNA sequencing in a rat model

Ischemia–reperfusion injury has been proven to induce organ dysfunction and death, although the mechanism is not fully understood. Long non-coding RNAs (lncRNAs) have drawn wide attention with their important ...

Coincidence cloning recovery of Brucella melitensis RNA from goat tissues: advancing the in vivo analysis of pathogen gene expression in brucellosis

Brucella melitensis bacteria cause persistent, intracellular infections in small ruminants as well as in humans, leading to significant morbidity and economic loss worldwide. The majority of experiments on the tr...

Positive cofactor 4 (PC4) contributes to the regulation of replication-dependent canonical histone gene expression

Core canonical histones are required in the S phase of the cell cycle to pack newly synthetized DNA, therefore the expression of their genes is highly activated during DNA replication. In mammalian cells, this...

Evaluation of suitable reference genes for qRT-PCR normalization in strawberry ( Fragaria  ×  ananassa ) under different experimental conditions

Strawberry has received much attention due to its nutritional value, unique flavor, and attractive appearance. The availability of the whole genome sequence and multiple transcriptome databases allows the grea...

Laser capture microdissection for transcriptomic profiles in human skin biopsies

The acquisition of reliable tissue-specific RNA sequencing data from human skin biopsy represents a major advance in research. However, the complexity of the process of isolation of specific layers from fresh-...

Targeting miR-9 in gastric cancer cells using locked nucleic acid oligonucleotides

Gastric cancer is the third leading cause of cancer-related mortality worldwide. Recently, it has been demonstrated that gastric cancer cells display a specific miRNA expression profile, with increasing eviden...

Quantitative profiling of BATF family proteins/JUNB/IRF hetero-trimers using Spec-seq

BATF family transcription factors (BATF, BATF2 and BATF3) form hetero-trimers with JUNB and either IRF4 or IRF8 to regulate cell fate in T cells and dendritic cells in vivo. While each combination of the heter...

pH-mediated upregulation of AQP1 gene expression through the Spi-B transcription factor

Bicarbonate-based peritoneal dialysis (PD) fluids enhance the migratory capacity and damage-repair ability of human peritoneal mesothelial cells by upregulating AQP1. However, little is known about the underly...

A protocol for custom CRISPR Cas9 donor vector construction to truncate genes in mammalian cells using pcDNA3 backbone

Clustered regularly interspaced short palindromic repeat (CRISPR) RNA-guided adaptive immune systems are found in prokaryotes to defend cells from foreign DNA. CRISPR Cas9 systems have been modified and employ...

The Correction to this article has been published in BMC Molecular Biology 2019 20 :20

Recommendations for mRNA analysis of micro-dissected glomerular tufts from paraffin-embedded human kidney biopsy samples

Glomeruli are excellent pre-determined natural structures for laser micro-dissection. Compartment-specific glomerular gene expression analysis of formalin-fixed paraffin-embedded renal biopsies could improve r...

Nutrient depletion and TOR inhibition induce 18S and 25S ribosomal RNAs resistant to a 5′-phosphate-dependent exonuclease in Candida albicans and other yeasts

Messenger RNA (mRNA) represents a small percentage of RNAs in a cell, with ribosomal RNA (rRNA) making up the bulk of it. To isolate mRNA from eukaryotes, typically poly-A selection is carried out. Recently, a...

An optimized rapid bisulfite conversion method with high recovery of cell-free DNA

Methylation analysis of cell-free DNA is a encouraging tool for tumor diagnosis, monitoring and prognosis. Sensitivity of methylation analysis is a very important matter due to the tiny amounts of cell-free DN...

Sumoylation in p27kip1 via RanBP2 promotes cancer cell growth in cholangiocarcinoma cell line QBC939

Cholangiocarcinoma is one of the deadly disease with poor 5-year survival and poor response to conventional therapies. Previously, we found that p27kip1 nuclear-cytoplasmic translocation confers proliferation ...

An optimised protocol for isolation of RNA from small sections of laser-capture microdissected FFPE tissue amenable for next-generation sequencing

Formalin-fixed paraffin embedded (FFPE) tissue constitutes a vast treasury of samples for biomedical research. Thus far however, extraction of RNA from FFPE tissue has proved challenging due to chemical RNA–pr...

Physical shearing imparts biological activity to DNA and ability to transmit itself horizontally across species and kingdom boundaries

We have recently reported that cell-free DNA (cfDNA) fragments derived from dying cells that circulate in blood are biologically active molecules and can readily enter into healthy cells to activate DNA damage...

Interaction between NFATc2 and the transcription factor Sp1 in pancreatic carcinoma cells PaTu 8988t

Nuclear factors of activated T-cells (NFATs) have been mainly characterized in the context of immune response regulation because, as transcription factors, they have the ability to induce gene transcription. N...

Splicing arrays reveal novel RBM10 targets, including SMN2 pre-mRNA

RBM10 is an RNA binding protein involved in message stabilization and alternative splicing regulation. The objective of the research described herein was to identify novel targets of RBM10-regulated splicing. ...

Growth arrest specific gene 2 in tilapia ( Oreochromis niloticus ): molecular characterization and functional analysis under low-temperature stress

Growth arrest specific 2 ( gas2 ) gene is a component of the microfilament system that plays a major role in the cell cycle, regulation of microfilaments, and cell morphology during apoptotic processes. However, li...

Identification of G-quadruplex structures that possess transcriptional regulating functions in the Dele and Cdc6 CpG islands

G-quadruplex is a DNA secondary structure that has been shown to play an important role in biological systems. In a previous study, we identified 1998 G-quadruplex-forming sequences using a mouse CpG islands D...

Mitochondrial RNA processing in absence of tRNA punctuations in octocorals

Mitogenome diversity is staggering among early branching animals with respect to size, gene density, content and order, and number of tRNA genes, especially in cnidarians. This last point is of special interes...

Microarray expression profiling in the denervated hippocampus identifies long noncoding RNAs functionally involved in neurogenesis

The denervated hippocampus provides a proper microenvironment for the survival and neuronal differentiation of neural progenitors. While thousands of lncRNAs were identified, only a few lncRNAs that regulate n...

Early growth response protein 1 regulates promoter activity of α -plasma membrane calcium ATPase 2, a major calcium pump in the brain and auditory system

Along with sodium/calcium (Ca 2+ ) exchangers, plasma membrane Ca 2+ ATPases (ATP2Bs) are main regulators of intracellular Ca 2+ levels. There are four ATP2B paralogs encoded by four different genes. Atp2b2 encodes t...

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Cell size and cell division mechanics

Guest edited by Shane McInally and Kristi Miller

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Keratin 19 binds and regulates cytoplasmic HNRNPK mRNA targets in triple-negative breast cancer

Genetic and protein interaction studies between the ciliary dyslexia candidate genes DYX1C1 and DCDC2

Myogenic differentiation of human myoblasts and Mesenchymal stromal cells under GDF11 on Poly-ɛ-caprolactone-collagen I-Polyethylene-nanofibers

Chromatin structure in cancer

In this new Review Wang et al. describe recent insights into altered genome architecture in human cancer, highlighting multiple pathways that disrupt chromatin structure and contribute to tumorgenesis.

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mTOR signaling pathway regulation HIF-1 α effects on LPS induced intestinal mucosal epithelial model damage

Authors: Zeyong Huang, Wenbin Teng, Liuxu Yao, Kai Xie, Suqin Hang, Rui He and Yuhong Li

Long non-coding RNA SOX2OT in tamoxifen-resistant breast cancer

Authors: Jeeyeon Lee, Eun-Ae Kim, Jieun Kang, Yee Soo Chae, Ho Yong Park, Byeongju Kang, Soo Jung Lee, In Hee Lee, Ji-Young Park, Nora Jee-young Park and Jin Hyang Jung

Mice lacking DIO3 exhibit sex-specific alterations in circadian patterns of corticosterone and gene expression in metabolic tissues

Authors: Zhaofei Wu, M. Elena Martinez and Arturo Hernandez

Optimization of seeding density of OP9 cells to improve hematopoietic differentiation efficiency

Authors: Xin-xing Jiang, Meng-yi Song, Qi Li, Yun-jian Wei, Yuan-hua Huang and Yan-lin Ma

Development of an in vitro human alveolar epithelial air-liquid interface model using a small molecule inhibitor cocktail

Authors: Ikuya Tanabe, Kanae Ishimori and Shinkichi Ishikawa

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Hypoxia-mimetic agents inhibit proliferation and alter the morphology of human umbilical cord-derived mesenchymal stem cells

Authors: Hui-Lan Zeng, Qi Zhong, Yong-Liang Qin, Qian-Qian Bu, Xin-Ai Han, Hai-Tao Jia and Hong-Wei Liu

Multiple immunofluorescence labelling of formalin-fixed paraffin-embedded (FFPE) tissue

Authors: David Robertson, Kay Savage, Jorge S Reis-Filho and Clare M Isacke

Caspase-9, caspase-3 and caspase-7 have distinct roles during intrinsic apoptosis

Authors: Matthew Brentnall, Luis Rodriguez-Menocal, Rebeka Ladron De Guevara, Enrique Cepero and Lawrence H Boise

Interleukin-1α enhances the aggressive behavior of pancreatic cancer cells by regulating the α 6 β 1 -integrin and urokinase plasminogen activator receptor expression

Authors: Hirozumi Sawai, Yuji Okada, Hitoshi Funahashi, Yoichi Matsuo, Hiroki Takahashi, Hiromitsu Takeyama and Tadao Manabe

Small molecule modulation of splicing factor expression is associated with rescue from cellular senescence

Authors: Eva Latorre, Vishal C. Birar, Angela N. Sheerin, J. Charles C. Jeynes, Amy Hooper, Helen R. Dawe, David Melzer, Lynne S. Cox, Richard G. A. Faragher, Elizabeth L. Ostler and Lorna W. Harries

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• v.46(11); 2017 Nov

Role of Molecular Biology in Cancer Treatment: A Review Article

1. Center of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan

Hafiza Yasara QAMAR

2. Institute of Molecular Biology and Biotechnology, University of Lahore, Lahore, Pakistan

Hafsa NAEEM

Mariam riaz, naila kanwal.

3. Dept. of Plant Breeding and Genetics, University of Agriculture, Faisalabad, Pakistan

4. Southern Cross Plant Science, Southern Cross University, Lismore, Australia

Muhammad Farooq SABAR *

5. Centre for Applied Molecular Biology, University of the Punjab, Lahore, Pakistan

Idrees Ahmad NASIR

Background:.

Cancer is a genetic disease and mainly arises due to a number of reasons include activation of onco-genes, malfunction of tumor suppressor genes or mutagenesis due to external factors.

This article was written from the data collected from PubMed, Nature, Science Direct, Springer and Elsevier groups of journals.

Oncogenes are deregulated form of normal proto-oncogenes required for cell division, differentiation and regulation. The conversion of proto-oncogene to oncogene is caused due to translocation, rearrangement of chromosomes or mutation in gene due to addition, deletion, duplication or viral infection. These oncogenes are targeted by drugs or RNAi system to prevent proliferation of cancerous cells. There have been developed different techniques of molecular biology used to diagnose and treat cancer, including retroviral therapy, silencing of oncogenes and mutations in tumor suppressor genes.

Conclusion:

Among all the techniques used, RNAi, zinc finger nucleases and CRISPR hold a brighter future towards creating a Cancer Free World.

Introduction

Cancer is a genetic disease. The expression of oncogenesis is an important event in early stages of tumor formation. Oncogenes are activated through two mechanisms: either by infection of cells by tumor viruses or by mutation of cellular proto-oncogenes (which are usually normal) to oncogenes. Then tumors originate by oncogenic transformation of only a single cell. Some tumors adopt the ability to escape the site of their origin and intrude other parts of the body. This process is called metastasis. Solid tumors i.e. sarcomas, could be transferred from one animal to another using Rous sarcoma virus. Tumors could be caused either by the addition or by expression of genetic material, which in this case was viral DNA, to normal cells. Rous was presented a Nobel Prize for his work. In 1978, tumors of nonviral origin were also discovered ( 1 ).

This article was written from the data collected from well-reputed `databases of PubMed, Science Direct, Springer and Elsevier groups of journals. The data were collected in the form of research and review articles on the use of molecular biology for cancer research, which was summarized to form an improved and advance review article. The following key words were used to search the databases: Cancer, Oncogenes, Proto-oncogenes, Mutagenesis, Viral infection, Tumor, CRISPR. Articles were verified published until 2015.

Results and discussion

Further, the relation between carcinogens and mutagens saying was described that many carcinogens are also mutagens. Mutations in normal genes might cause them to become cancerous and this could happen due to any damage to DNA. This hypothesis got further support after molecular biology tools were applied in cancer research ( 2 ). Other than expression of oncogenes, cancer may also arise due to the loss or damage of tumor suppressor genes that check and control the cell growth. In many cases, both reasons contribute to causing cancer ( 3 ).

Oncogenes in cancer development

Oncogenes are the tumor causing genes and have important role in development of many cancers. In 1970, SRC oncogene was discovered in chicken retrovirus. As a result of some mutation in the otherwise normal proto-oncogenes, their deregulation occurs and uncontrolled proliferation of cells starts and leads to cancer ( 4 ). At genomic level, only single oncogenic allele is required to alter normal gene function because of its dominant property. The origin of oncogene can be cellular i.e., from inside the body or viral i.e., from some virus ( 3 ).

Gene Duplication, addition, insertion, deletion or chromosomal translocation, chromosomal rearrangement of certain proto-oncogenes alters their function and converts them into oncogenes. These mutations overexpress the protein to an uncontrolled level, which may lead to tumor. These mutations may occur due to external factors or internal factors or both like viral infection, radiation or chemicals, injury and disease ( 4 ). Among these mutations, viral infection is the rare cause of oncogene activation in animals but is of great importance for understanding oncogene function.

Viral infection

Retroviruses or DNA viruses cause viral infections. These viruses infect the host either by inserting oncogenes in host chromosome, interfering proto-oncogene transcription factors/regulators or by inserting homologous sequences corresponding to normal protooncogene of host. For example, retrovirus carrying SRC oncogenes infects the host, integrates viral chromosome in host chromosome, further divides the viral progeny and infects the surrounding cells, inducing overexpression of cellular normal genes and deregulated proliferation of cells in order to cause cancer ( 5 ).

Types and classification of oncogenes:

Oncogenes can be classified into five classes based on protein products formed by mutation or deregulation of proto-oncogenes. These include growth factors, growth hormone/factor receptors (GRFs), serine/threonine kinases, GTPase molecules and, transcription factors. Mutations in the growth factors can lead to several types of cancers such as fibrosarcoma, glioblastoma (brain cancer), osteosarcoma (bone cancer) etc. ( 6 , 7 ).

In several tumors, “ligand-binding domain” deletions of Epidermal Growth Factor Receptor cause successive activation of receptor even in absence of ligand by transmembrane protein carrying tyrosine-kinase activity. This activation causes interaction with further cytoplasmic proteins like “SRC domain” and leads to deregulation of numerous signaling pathways. Mostly in gastrointestinal, breast and lung cancers, GFR mutations occur ( 4 ). Similarly, overexpression of Raf-1 kinase and cyclin-dependent kinases due to uncontrolled phosphorylation may cause many cancers such as thyroid and ovarian cancer.

Deregulated activation of GTPases such as Ras, causes activation of MAPK pathway and uncontrolled signaling and division of cells cause several cancers such as myeloid leukemia. Transcription factor proteins are products of protooncogenes. The mutation, translocation or rearrangement of these causes overexpression of gene and unwanted consecutive transcription of target gene that leads to any types of cancers such as pancreatic and lung cancer ( 6 ).

Role of oncogenes to treat cancer

The oncogenes are targeted to treat oncogenic cancer. Several oncogenes discussed above are targeted by drugs and gene therapies to inhibit, arrest, regulate or senescence their genes. For example, Imatinib (ABL kinase inhibitor) or Gleevec is used to treat BCR-ABL. Gefitinib or Iressa, erlotinib or Tarceva are used to target EGFR. VEGF oncogenes are targeted by bevacizumab or sorafenib. Sorafenib is also used to downregulate or inhibit B-Raf oncogene. These agents/drugs are used, sometimes in combination, for chemotherapy to inhibit proliferation of oncogenes or to downregulate signaling oncoproteins in several signaling pathways to treat oncogenic cancers ( 8 ). However, it is difficult to target “non-kinase oncogenes” through drugs such as Myc and Ras.

Tumor suppressor genes in cancer

Tumor suppressors play their role by inhibiting cellular proliferation and tumor development. In most of the tumors, inactivation of the tumor suppressor genes eliminates the negative regulation of these genes over cellular proliferation that leads to abnormal cell proliferation, therefore, causing cancer. Tumor suppressor genes have “loss of function” mutations because they develop cancer by inactivating their inhibitory effect on cell proliferation. For a tumor suppressor gene to promote tumor development, both copies of the gene must be inactivated because one copy is sufficient for controlling cell proliferation. These mutations act recessively ( 9 ).

Role of Tumor Suppressor Genes

The protein products tumor suppressing genes are found to play the following important functions:

• Enzymes involved in DNA repair
• Checkpoint-control proteins arresting the cell cycle in case DNA is impaired or chromosome abnormality.
• Proteins promoting programmed cell death (apoptosis)
• Inhibiting cellular growth and proliferation by acting as receptors for hormones.
• Intracellular proteins which regulate or inhibits movement through a specific stage of cell cycle ( 10 ).

Role of Tumor Suppressor Genes in Cancer Wilms’ Tumor 1 Gene

Some tumor-suppressing genes act as transcriptional regulatory proteins. For example, the product of WT1 gene which is a repressor protein and acts by suppressing transcription of many growth factor-inducible genes. WT1 is made inactive in Wilms’ tumors (which is a tumor in kidney found in children). Insulin-like growth factor II is the target of WT1 gene, over-expressed in Wilms’ tumors, thereby contributing to abnormal cell proliferation ( 11 ).

Retinoblastoma and INK4 Genes

Several tumor suppressor genes regulate cell cycle progression through a specific stage e.g. protein products of Rb and INK-4 genes. Retinoblastoma is the tumor of the eye. Two mutagenic events are required for the retinoblastoma development in sporadic cases whereas only one mutagenic event is needed in individuals with inherited form of the disease in which it displays autosomal dominant inheritance. In normal cells, Cdk2 and cyclin D complexes regulate the entry through the constraint point, thereby phosphorylating and inactivating pRb. pRb also impedes the entry through the constraint point in the G 1 phase of the cell cycle by repressing the transcription of many genes involved in cell cycle advancement. The INK4 tumor suppressor gene also regulates movement through the restriction point by encoding Cdk inhibitor p16. Inactivation of INK4 results in uncontrolled phosphorylation of Rb ( 10 ).

p53 Tumor Suppressor Gene

The p53 plays its role by regulating cell cycle and programmed cell death. The p53 can arrest the cell cycle upon DNA damage. It allows the DNA to repair or cause the programmed cell death (apoptosis). This is achieved by activating a number of genes involved in controlling and regulating the cell cycle. Mutation in p53 in tumorigenic cells results in uncontrolled cell proliferation and inefficient DNA repair. p53 mutations are estimated to be the most common in tumors of humans, approximately 50% or even greater than that ( 12 ).

Breast Cancer-1 and 2 Genes

Breast cancer-1 and 2 genes are linked to familial breast cancer. Breast Cancer-1 gene consists of 100 Kb DNA and 21 exons. It has a zinc-finger domain like that in the DNA binding proteins. Breast cancer-1 is a tumor suppressor gene. BRCA-2 is located on chromosome 13.

Tumor Suppressor Genes and their application

Tumor suppressor genes can be studied at the levels of DNA, mRNA, and proteins in the normal and cancerous cells using various methods. Tests for the detection of heterozygosity can be helpful for identifying individuals predisposed to retinoblastoma and other malignancies. Higher frequency of p53 mutations also offers diagnostic and analytical possibilities. PCR amplification can be used to study the changes along with recent methods such as RNase protection assays, single-strand conformational polymorphism or denaturing gel electrophoresis. Immunometric–type assays are quite good at measuring altered p53 in tumor cell line lysates and tissue homogenates ( 13 , 14 ).

Molecular pathology: Diagnosis of cancer

One of the primary challenges in the clinical management of cancer patients is to establish the correct diagnosis. As a result, a number of technologies have been developed and are now routinely employed to subtype molecularly cancers. These include immunohistochemistry, immunofluorescence, and the analysis of DNA and RNA extracted from the lesion-through In situ hybridization and fluorescent in situ hybridization (FISH). The cancer specimen is then subtyped using different approaches of molecular biology including Sanger sequencing, pyrosequencing, allele-specific PCR. Cancer genotyping is performed by snapshot assay, mass spectroscopy based assays and next generation sequencing (based on fluorescence or semiconductor detectors). The introduction of next-generation sequencing is serving to uncover the true diversity of cancers as well as to define recurring mutations targeted with new therapies. Such genomic-level analyses will continue to have an impact for many years ( 15 , 16 ).

Cancer treatment – then & now

Different treatment techniques and therapies have been applied for the treatment of cancer at different times. Some of the most common methods used include surgery, radiation therapy, chemotherapy, hormonal therapy, immunotherapy, adjuvant therapy, targeted-growth signal inhibition, drugs that induce apoptosis, nanotechnology, RNA expression and profiling, and the latest being CRISPR ( 17 ). Few of these shall be later discussed in this review.

Cancer cells can also be killed by gene replacements or by knocking out oncogenes. Oncolytic viruses can be used in combination with chemo-therapeutic agents to destroy cancer cells as well ( 18 ).

Retroviral therapy for cancer

Apart from the conventional methods, retroviruses (RVs) have also been used in cancer therapy. RVs can be and have been used for transferring genes to mammalian cells. Most popular RVs are the ones derived from the Moloney Murine leukaemia virus (MoMLV). In the last twenty years, artificial evolution of RVs has enabled their applications in developing transgenic animals, stable delivery of siRNA and clinical trials for gene therapy. The great potential of RVs was discussed in recent reports about the successful clinical trials of gene therapy in patients with severe immunodeficiency disease. However, there are some probable risks inherently related with that ( 19 ). A comparative experiment was done by designing two groups of vectors. One was intrinsically replicative, the other was defective and so it had a helper retrovirus with it. Under in vitro conditions, the replicative viruses achieved more than 85% transduction while the other transduced only less than 1%. This experiment clearly indicates the potential of RRVs for developing cancer gene therapy ( 20 ).

Retroviral tagging and insertional oncogenesis

Recently, interest in investigating retroviral vector insertions (insertional oncogenesis) has been growing. For many years, viral insertion sites were used to identify possible oncogenes and cancer signaling pathways. The scope of this approach has been broadened by techniques like insertion site cloning by high throughput PCR, availability of genetically modified animals and with the completion of mouse genome project ( 21 , 22 ). However, numerous investigators have identified hundreds of common sites. These integration sites are usually associated with cancer genes in MoMLV-induced murine haematopoietic malignancies ( 23 – 25 ). Generally, majority of the insertions exist outside the coding regions. Therefore, only less than 10% of the RISs can be considered as the accepted tumor suppressor genes. Quite interestingly, around 17%–18% of RISs are targeted transcription factors ( 19 ).

Problems with Retroviral Therapy

There are some safety concerns associated with the retroviral gene therapy addressed. Some possible solutions to this problem could be targeted infection, transcriptional targeting, local delivery, co-transduction of retroviral vector with a suicidal gene, specifically targeted retroviral insertion, and SIN vectors. These procedures, with both viral and non-viral systems, can be used in protocols for gene therapy. Nevertheless, insertional oncogenesis remains the major concern regarding retroviral gene therapy ( 26 ). A safe and fast means of targeted approach could be the use of foamy viruses ( 27 , 28 ). These viruses are harmless to humans and yet have a wide range of hosts ( 29 – 31 ). However, for ex vivo cell-based gene therapy, insertional oncogenesis can be avoided by pre-screening of transduced cells in order to select only those cells (clones) which have the transgene only at a desirable site of the chromosome ( 26 ).

Molecular biology techniques for the treatment of cancer

Initially, homologous recombination was used to inactivate the target gene. This was done for characterizing the function of genes. This method was not as productive as it was not efficient in introducing constructs onto the target site. It was very lengthy process, the selection process was laborious and there were many severe mutagenic effects of this method ( 32 ).

RNA Interference

One of the methods used in cancer therapy is RNA interference. RNA interference involves the use of small non-coding RNA that can bind with other mRNAs and can inhibit their translation into proteins. This can result in the loss of function of genes. In cancer therapy, these RNAi can be used to destroy the function of cancer genes that prevent cancer from spreading ( 33 – 35 ). The RNAi method is fast, cheap and it has a high efficiency so it replaced homologous recombination method. Still, it has drawbacks that include incomplete knockdown and temporary prevention of gene function. It also gives off-target effects unpredicted. Cancer recurrence was also seen in some cases. All these problems lead the researchers to explore new methods to alter the gene function ( 36 ).

Genome editing is a far better and new technique to treat cancer. Scientists used engineered nucleases that have specific domains that can bind to the target site followed by its cleavage ( 37 , 38 ). These nucleases were able to induce double-strand breaks (DSBs) in the target followed by the activation of DNA repair mechanisms. Two types of nucleases are used that include programmable nucleases like Zinc Finger Nucleases (ZFNs) and transcription-activator-like effector nucleases (TALENs). These nucleases were successful in genome editing for curing cancer in different animal models ( 39 ).

Zinc finger proteins (ZNFs)

Znfs are the first nucleases to be used for gene editing.

These are found as DNA binding domains in eukaryotes. These are made up of 30 amino acids modules arranged in the form of an array of Cys2-His2 DNA-binding zinc fingers. These modules are used to a nuclease domain of FokI ( 37 , 40 , 41 ). The modules consist of 3–6 zinc fingers that can identify nucleotide triplets ( 42 , 43 ). The FokI nuclease functions only as dimers so a pair of zinc finger nucleases is needed to target any region in the genome. One ZFN will identify the sequence upstream of the genome region to be modified and other will identify downstream sequence ( 44 ). These arrays bind to nearby DNA sequences that are in the opposite strands to induce a double-stranded break in the specific region. The breaks are then repaired by different methods that can cause different changes in the specific region like point mutations, indels or translocations. The ZNFs are custom designed so that they recognize all possible nucleotides and any specific region of DNA. ( 42 , 45 , 46 ).

Transcription activator-like effector nucleases (TALENs)

TALENs are similar to zinc finger nucleases, as they also need DNA binding motifs and the same nuclease to edit the genome. The difference lies in the recognition of nucleotides as the TALENs domain identifies only one nucleotide instead of a triplet. The interactions between the TALEN domains and their target sites are stronger as compared to ZNFs. It is easier to design TALENs as compared to designing of ZNFs ( 46 , 47 ). Using TALENs for cancer therapy is very effective method. It needs two specifically engineered TALENs that can identify the sequences of DNA in the target gene on the opposite strands. It dimerizes the FokI nuclease cleavage domain in the TALENs, cleaving the sequence in the target gene ( 48 – 50 ). This causes double-stranded DNA breaks in the targeted gene. The lesion due to the DNA break is repaired by the end-joining DNA repair system. The target gene is altered due to the change in the reading frame. This method can also be used to remove the already present mutations. This gene editing technology can be used to treat the cancer cell lines efficiently as it can target any gene in the genome. Complex cancer genes can be treated by using TALENs ( 51 ).

CRISPR/CAS9 system: A powerful tool for genome editing in cancer

A powerful genome-editing technology known as Clustered regularly interspaced palindromic sequences-acronym CRISPR, is now eclipsing all other genome-engineering techniques. This revolutionary technique allows researchers to accomplish targeted manipulation in any gene (DNA sequence) in the entire genome of any organism in vitro or now even directly in endogenous genome, thus helping to elucidate the functional organization of genome at systems level and identifying casual genetic variations. CRISPR plays a vital role in detection of cancers ( 52 ).

Mechanism of CRISPR-Cas9 in cancer treatment

If cancer causing gene is known, cancerous cells can be treated with CRISPR-Cas9 system which helps in gene deletion and replacement with a normal gene. Yin et al in his paper discuss the injection process using CRISPR-Cas9 system to cut and introduce gene into liver cells. CRISPRCas9 is more effective for single gene mutation cancers and is mostly delivered in vitro in a particular location. In case of metastatic cancers, in vitro delivery becomes difficult. CRISPR primarily constitutes two biological components: Engineered single guide RNA (sgRNA) and Cas9. A small guide RNA (crRNA and tracrRNA) is used to recognize the complementary sequence-specific target flanked by proto-spacer adjacent motif (PAM) and it guides endonucleases i.e. Cas9 to cleave this sequence ( 53 ). Different CRISPR-Cas systems have been grouped majorly into three types (I–III) and subtypes (as I-E) depending on diverse bacterial and archeal repeat sequences, as genes, and their mode of action ( 54 ). Type I and III systems share a common mechanism of processing of pre-crRNAs (to crRNA) via specialized Cas endonucleases, and on maturation, each crRNA complex with multi-Cas protein is capable of recognizing and cleaving target sequences which are complementary to crRNA. In contrary to this, Type II system is considered the heart of genome engineering tool because it involves reduced number of Cas enzymes ( Fig. 1 ).

Natural mechanisms of microbial adaptive immune CRISPR Systems: 1. Phage infection, 2. Spacer acquisition, 3. cRNA biogenesis, and processing ( 52 )

It requires non-coding tracrRNA which triggers the processing of pre-crRNA via dsRNA specific Ribonuclease RNase III and cas9 protein (only protein carrying out effective crRNA-mediated silencing of target) ( 55 ). CRISPR loci are predominantly composed of multiple repeated sequences (approx. 21–48 bp) interspaced by variable spacer sequences (approx. of 2–72 bp) and Cas genes situated alongside CRISPR locus. First, this CRISPR locus array is transcribed as single RNA, processing of this released pre-RNA (from within repeat sequences) into singular shorter units of CRISPR RNAs (crRNAs) using host proteins is done. Mature crRNA effectively binds to nucleases i.e. Cas proteins, thus this complex of crRNA-cas9 helps in recognizing and then cleaving the target invading DNA or RNA having complementarity to crRNA (sites called protospacers). A motif of 2–5 nucleotide called as PAM is located alongside protospacer in CRISPR-Cas systems I & II ( 54 ). PAM, a nucleic acid sequence made up of NGG or NAG trinucleotide for Cas9, flanks at 3’ end of the DNA target site, helps Cas9 in its specific cleavage activity and also facilitates Cas9 in distinguishing self-versus non self-bacterial sequences as PAM ( 52 ). SpCas9 (called as Streptococcus pyogenes Cas9) is being in use currently for effective genome editing in eukaryotic organisms including humans. PAM located downstream of target is only sequence allowing cas9 target site selection. Cas9 proteins vary in their size and sequence and have common domains as HNH and RuvC endonuclease to cleave two strands of target DNA ( Fig. 2 ).

Genome editing via CRISPR-Cas9 system. a) Double-strand breaks in DNA sequence can be repaired by cellular DNA repair mechanisms: the non-homologous end joining (NHEJ) or homology-directed repair (HDR)

Cas9HNH domain is specified for cleavage of strand complementary to guide (target) sequence while Cas9 RuvC domains for non-complementary (non-target) strand, In addition, Cas9 holds some conserved arginine-rich sites for binding of nucleic acid ( 53 ). Target recognition by this crRNA directs the silencing of foreign sequences by means of case proteins that function in complex with crRNAs ( 52 , 54 ).

The Streptococcus pyogenes-derived CRISPR–Cas9 RNA-guided DNA endonuclease is localized to a specific DNA sequence via a single guide RNA (sgRNA) sequence, which base pairs with a specific target sequence that is adjacent to a protos-pacer adjacent motif (PAM) sequence in the form of NGG or NAG.

On induction of double-stranded breaks or nicks at targeted regions, repairing is done by either Non-homologous end joining (NHEJ) or Homology-directed repair (HDR) pathway . NHEJ is an error-prone repair mechanism where joining of broken ends takes place, which generally results in heterogeneous indels (insertions and deletions) whereas HDR is a precise repair method in which homologous donor template DNA is being used in repair DNA damage target site ( 53 ).

Advantages of CRISPR over traditional methods

The CRISPR/Cas9 system is preferred over the ZNFs and TALENs because of many advantages. Firstly, the target design process is simpler for CRISPR as it depends upon the ribonucleotide complex formation instead of DNA recognition. It can be designed easily and it is much cheaper than designing nucleases as this does not need different proteins for each target and eliminates laborious cloning steps. This can be used to target any specific sequence in the genome. The CRISPR system is much more efficient than ZFNs and TALENs. The RNA encoding Cas protein can be injected directly for modifying the host genome. It is not so lengthy and laborious process as compared to traditional methods ( 12 , 51 ). By using CRISPR, we can introduce multiplexed mutations. Many genes can be mutated simultaneously by injecting with many gRNAs. This process is faster as compared to other methods. It does not introduce sensitivity to DNA methylation so it can be used if the target site is GC rich.

Molecular biology has rapidly evolved in the last decade than it has ever before. Different cancer treatment techniques are emerging and succeeding and with the development of ZNFs, TALENs, and CRISPR, scientists are able to target any sequence in the genome, even multiple genes. This will provide immense help in the treatment of diseases like cancer, avoiding the risks caused by the previous methods.

Ethical considerations

Ethical issues (Including plagiarism, informed consent, misconduct, data fabrication and/or falsification, double publication and/or submission, redundancy, etc.) have been completely observed by the authors.

Acknowledgments

The study was carried without financial support from any government or other educational organization. The authors acknowledged Dr. Idrees Ahmad Nasir and Dr. Muhammad Farooq Sabar for helping in editing of manuscript.

Conflict of interests

The authors declare that there is no conflict of interest.

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A universal framework for spatial biology

by Luca Marconato, Kevin Domanegg and Lisa Vollmar, European Molecular Biology Laboratory

Biological processes are framed by the context they take place in. A new tool developed by the Stegle Group from EMBL Heidelberg and the German Cancer Research Center (DKFZ) helps put molecular biology research findings in a better context of cellular surroundings, by integrating different forms of spatial data.

In a tissue, every individual cell is surrounded by other cells, and they all constantly interact with each other to give rise to biological function. To understand how tissues work or malfunction in diseases such as cancer, it is crucial to not only learn the characteristics of every cell, but also account for their spatial context. Quantitative characterization of cells in the context of the physical space they inhabit is key to understanding complex systems.

The technologies enabling these types of exploration are called spatial omics technologies, and their progressing development is contributing to the rise in popularity of spatial biology. Such technologies can give detailed information about the molecular makeup of individual cells and their spatial arrangement.

However, these technologies focus on different characteristics of a cell—such as RNA or protein levels, and the resulting datasets are managed and stored in diverse ways. To solve this challenge, a collaborative project led by the Stegle Group developed SpatialData, a data standard and software framework which allows scientists to represent data from a wide range of spatial omics technologies in a unified manner.

Technology development for spatial biology

Over the last decade, numerous technologies have been developed by both academia and industry for spatially visualizing tissues, cells, and subcellular compartments. However, each technique focuses on a small number of desirable characteristics and presents related trade-offs. For instance, Visium from 10x Genomics captures information about the expression of all genes in a tissue, but does not provide single-cell resolution.

In contrast, the 10x Genomics Xenium assay, MERFISH, or the MERSCOPE platform from Vizgen yield fine-grained maps of gene expression with subcellular resolution. However, these assays are currently limited to a few hundred preselected genes. And the list of such technologies, each providing a small slice of the full picture, keeps growing.

Challenges of spatial omics technologies

This heterogeneity of technologies is reflected on the computational side by an even greater heterogeneity of file formats: each technology comes with its own storage format, and often data generated by the same technology can be stored in multiple formats.

Practically, this brings several challenges to the analysis of spatial omics data. Visualization and analysis methods are usually tailored to a specific technology, which limits data compatibility and makes it hard to integrate different methods into a single analysis pipeline. However, for a holistic understanding of a biological system, it's important to simultaneously look at different cell characteristics or samples from different locations.

Omics technologies generate enormous amounts of data (terabytes of images, millions of cells, billions of single molecules), demanding optimized engineering solutions. Hence, spatial biology urgently needs a universal framework that can integrate data across experiments and technologies, and provide holistic insights into health and disease. This is where SpatialData steps in.

SpatialData—a framework to unite them all

"There is a strong need to establish community solutions for the management and storage of spatial omics data. In particular, there is a need to develop new data standards and computational foundations that allow for unifying analysis approaches across the full spectrum of different spatial omics technologies that are emerging," said Oliver Stegle, Group Leader at EMBL in the Genome Biology Unit, and head of the Computational Genomics and Systems Genetics division at the German Cancer Research Center (DKFZ).

"A first major step in this direction is SpatialData, a data standard and software framework that bridges and adapts previous data management concepts from single-cell multi-omics to the spatial domain."

SpatialData unifies and integrates data from different omics technologies, bridging state-of the-art-technologies with a framework that allows for computationally performant access and manipulation of the data.

This tool was introduced in a Nature Methods publication , authored by Luca Marconato during his Ph.D. at EMBL in the Stegle Group, a joint degree with the Faculty of Bioscience of the University of Heidelberg.

"We developed the SpatialData framework to alleviate the data representation challenges when studying spatial biology, so that the researcher can focus on the biological analysis, rather than being slowed down by tedious data manipulations, otherwise required to even just visualize the data. The framework provides a unified representation and implements ergonomic operations for convenient processing of spatial omics data," said Marconato.

The tool enables any researcher to import their data and perform tasks like data representation, processing, and visualization. Additionally, it gives the option to interactively annotate the data, and save it in a language-agnostic format, facilitating the emergence of analysis strategies that combine methods from different programming languages or analysis communities.

The framework has been developed as a collaborative project between multiple institutions such as the DKFZ, the Technical University of Munich, the Helmholtz Center Munich, German BioImaging, the ETH Zürich, VIB Center for Inflammation Research in Belgium, as well as the Huber and Saka groups at EMBL.

"We have conducted our research and technological development keeping the benefit for the bigger science community in mind," said Giovanni Palla, co-first author and Ph.D. student at the Helmholtz Center Munich.

"We not only established an interdisciplinary collaboration project between research institutes but also worked closely with developers working with different spatial technologies and in different programming languages to address the problem of interoperability. As a result, our framework is compatible with the vast majority of spatial omics assays from academia and industry.

"Being published openly, other researchers can now freely use SpatialData to manage their own data and have the opportunity to collaborate across various technologies and research topics."

"In our paper, we illustrate three important features of SpatialData," explained Kevin Yamauchi, co-first author and a postdoctoral researcher at ETH Zürich.

"First, we present a standardized interface and unified storage format (based on the OME-NGFF) for all spatial omics technologies. Second, using the unified representation, we integrate signals from multiple modalities. Here, we transfer annotations across modalities and quantify signals using these transferred annotations. Finally, we present a way to interactively annotate (pathology) images and use the annotations to analyze the associated molecular profiles."

SpatialData provides an interactive representation of data, both on your hard drive and your computer's RAM, which enables the analysis of large imaging data or multiple geometries or cells.

Other prominent key features are the framework's ability to align and annotate omics data in a common coordinate system. Thus, SpatialData enables the efficient management and manipulation of spatial datasets, including the definition of a common coordinate system across sequencing- and imaging-based technologies.

Application in breast cancer

The interdisciplinary team used the SpatialData framework to reanalyze a multimodal breast cancer dataset from 10X Genomics as a proof of concept. This dataset comprises consecutive sections of the same breast cancer block, where each section is analyzed using different technology, like Visium, Xenium, and a separate scRNA-seq dataset.

The study demonstrates the complementary nature of these technologies. "By integrating 10X Xenium and scRNAseq, we mapped the cell types into the space," said Elyas Heidari, a Ph.D. candidate at DKFZ and one of the authors of the study.

"Next, we used 10X Visium to identify cancer clones in space. This can be done because we have transcriptome-wide readouts. Finally, we used the H&E stained microscopy images to identify regions of interest for histopathology annotations. This analysis successfully showcased a unique application of SpatialData in unlocking multi-modal analyses of spatially-resolved datasets."

In the future, a patient's tumor might be analyzed with different technologies commonly used in the clinic, with the data then unified by SpatialData to gain a holistic understanding of the tumor. Furthermore, the interactive interface would allow the doctor to annotate the data, thus enabling detailed analysis of specific tumor regions and characteristics, potentially leading to personalized treatment approaches.

Journal information: Nature Methods

Provided by European Molecular Biology Laboratory

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Maternal factor Trim75 contributes to zygotic genome activation program in mouse early embryos

• Original Article
• Published: 20 April 2024
• Volume 51 , article number  560 , ( 2024 )

Cite this article

• Weibo Hou 1   na1 ,
• Lijun Chen 1   na1 ,
• Jingzhang Ji 1   na1 ,
• Songling Xiao 1 ,
• Hongye Linghu 1 ,
• Lixin Zhang 1 ,
• Yue Ping 3 ,
• Chunsheng Wang 3 ,
• Qingran Kong 1 ,
• Wenpin Cai 2 &
• Xu Yang   ORCID: orcid.org/0009-0005-1359-7613 1  

17 Accesses

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Zygotic genome activation (ZGA) is an important event in the early embryo development, and human embryo developmental arrest has been highly correlated with ZGA failure in clinical studies. Although a few studies have linked maternal factors to mammalian ZGA, more studies are needed to fully elucidate the maternal factors that are involved in ZGA.

Methods and results

In this study, we utilized published single-cell RNA sequencing data from a Dux-mediated mouse embryonic stem cell to induce a 2-cell-like transition state and selected potential drivers for the transition according to an RNA velocity analysis.

Conclusions

An overlap of potential candidate markers of 2-cell-like-cells identified in this research with markers generated by various data sets suggests that Trim75 is a potential driver of minor ZGA and may recruit EP300 and establish H3K27ac in the gene body of minor ZGA genes, thereby contributing to mammalian preimplantation embryo development.

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Data availability

All sequencing data of mouse embryos generated in this study have been deposited in GEO under accession GSE227385.

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The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Author information

Weibo Hou, Lijun Chen and Jingzhang Ji contributed equally to this work and share first authorship.

Authors and Affiliations

School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang Province, China

Weibo Hou, Lijun Chen, Jingzhang Ji, Songling Xiao, Hongye Linghu, Lixin Zhang, Qingran Kong & Xu Yang

Department of Laboratory Medicine, Wenzhou Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medicine University, Wenzhou, Zhejiang, People’s Republic of China

College of Life Science, Northeast Forestry University, No. 26, hexing Road, Harbin, China

Yue Ping & Chunsheng Wang

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Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Weibo Hou, Lijun Chen, Jingzhang Ji, Songling Xiao, Hongye Linghu, Lixin Zhang, Yue Ping and Chunsheng Wang. The first draft of the manuscript was written by Xu Yang and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Qingran Kong , Wenpin Cai or Xu Yang .

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Hou, W., Chen, L., Ji, J. et al. Maternal factor Trim75 contributes to zygotic genome activation program in mouse early embryos. Mol Biol Rep 51 , 560 (2024). https://doi.org/10.1007/s11033-024-09349-0

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DOI : https://doi.org/10.1007/s11033-024-09349-0

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HYPOTHESIS AND THEORY article

This article is part of the research topic.

Using Case Study and Narrative Pedagogy to Guide Students Through the Process of Science

Molecular Storytelling: A Conceptual Framework for Teaching and Learning with Molecular Case Studies Provisionally Accepted

• 1 School of Interdisciplinary Arts and Sciences, University of Washington Bothell, United States
• 2 Institute for Quantitative Biomedicine, Rutgers, The State University of New Jersey, United States
• 3 Research Collaboratory for Structural Bioinformatics Protein Data Bank, Rutgers, The State University of New Jersey,, United States

The final, formatted version of the article will be published soon.

Molecular case studies (MCSs) provide educational opportunities to explore biomolecular structure and function using data from public bioinformatics resources. The conceptual basis for the design of MCSs has yet to be fully discussed in the literature, so we present molecular storytelling as a conceptual framework for teaching with case studies. Whether the case study aims to understand the biology of a specific disease and design its treatments or track the evolution of a biosynthetic pathway, vast amounts of structural and functional data, freely available in public bioinformatics resources, can facilitate rich explorations in atomic detail. To help biology and chemistry educators use these resources for instruction, a community of scholars collaborated to create the Molecular CaseNet. This community uses storytelling to explore biomolecular structure and function while teaching biology and chemistry. In this article, we define the structure of an MCS and present an example. Then, we articulate the evolution of a conceptual framework for developing and using MCSs. Finally, we related our framework to the development of technological, pedagogical, and content knowledge (TPCK) for educators in the Molecular CaseNet. The report conceptualizes an interdisciplinary framework for teaching about the molecular world and informs lesson design and education research.

Keywords: Molecular education, Case studies, Technological pedagogical and content knowledge (TPCK), Molecular structure and function, molecular visualization, Bioinformatics education, conceptual modeling

Received: 31 Jan 2024; Accepted: 23 Apr 2024.

Copyright: © 2024 Trujillo and Dutta. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Caleb M. Trujillo, University of Washington Bothell, School of Interdisciplinary Arts and Sciences, Bothell, United States

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