scholarly journals Transgenic mouse models in the study of reproduction: insights into GATA protein function

Reproduction ◽  
2014 ◽  
Vol 148 (1) ◽  
pp. R1-R14 ◽  
Author(s):  
Sergei G Tevosian
Keyword(s):  
Protein Function ◽  
Transcriptional Control ◽  
Cell Types ◽  
Regulatory Elements ◽  
Genetically Engineered ◽  
Detailed Knowledge ◽  
P Gene ◽  
Genes Encoding ◽  
Key Factor ◽  
Dna Regulatory Elements

For the past 2 decades, transgenic technology in mice has allowed for an unprecedented insight into the transcriptional control of reproductive development and function. The key factor among the mouse genetic tools that made this rapid advance possible is a conditional transgenic approach, a particularly versatile method of creating gene deletions and substitutions in the mouse genome. A centerpiece of this strategy is an enzyme, Cre recombinase, which is expressed from defined DNA regulatory elements that are active in the tissue of choice. The regulatory DNA element (either genetically engineered or natural) assures Cre expression only in predetermined cell types, leading to the guided deletion of genetically modified (flanked by loxP or ‘floxed’ byloxP) gene loci. This review summarizes and compares the studies in which genes encoding GATA family transcription factors were targeted either globally or by Cre recombinases active in the somatic cells of ovaries and testes. The conditional gene loss experiments require detailed knowledge of the spatial and temporal expression of Cre activity, and the challenges in interpreting the outcomes are highlighted. These studies also expose the complexity of GATA-dependent regulation of gonadal gene expression and suggest that gene function is highly context dependent.

scholarly journals A scalable platform for the development of cell-type-specific viral drivers

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Sinisa Hrvatin ◽  
Christopher P Tzeng ◽  
M Aurel Nagy ◽  
Hume Stroud ◽  
Charalampia Koutsioumpa ◽  
...  
Keyword(s):  
Gene Expression ◽  
Heterologous Gene Expression ◽  
High Specificity ◽  
Cell Types ◽  
Regulatory Elements ◽  
Cell Type ◽  
Cell Type Specificity ◽  
Cell Type Specific ◽  
The Many ◽  
Dna Regulatory Elements

Enhancers are the primary DNA regulatory elements that confer cell type specificity of gene expression. Recent studies characterizing individual enhancers have revealed their potential to direct heterologous gene expression in a highly cell-type-specific manner. However, it has not yet been possible to systematically identify and test the function of enhancers for each of the many cell types in an organism. We have developed PESCA, a scalable and generalizable method that leverages ATAC- and single-cell RNA-sequencing protocols, to characterize cell-type-specific enhancers that should enable genetic access and perturbation of gene function across mammalian cell types. Focusing on the highly heterogeneous mammalian cerebral cortex, we apply PESCA to find enhancers and generate viral reagents capable of accessing and manipulating a subset of somatostatin-expressing cortical interneurons with high specificity. This study demonstrates the utility of this platform for developing new cell-type-specific viral reagents, with significant implications for both basic and translational research.

scholarly journals Dysregulated Transcriptional Control in Prostate Cancer

2019 ◽  
Vol 20 (12) ◽  
pp. 2883 ◽  
Author(s):  
Simon J. Baumgart ◽  
Ekaterina Nevedomskaya ◽  
Bernard Haendler
Keyword(s):  
Prostate Cancer ◽  
Drug Targets ◽  
Transcriptional Control ◽  
Regulatory Elements ◽  
Protein Coding ◽  
Coding Regions ◽  
Super Enhancer ◽  
Position Coding ◽  
Transcription Dysregulation ◽  
Dna Regulatory Elements

Recent advances in whole-genome and transcriptome sequencing of prostate cancer at different stages indicate that a large number of mutations found in tumors are present in non-protein coding regions of the genome and lead to dysregulated gene expression. Single nucleotide variations and small mutations affecting the recruitment of transcription factor complexes to DNA regulatory elements are observed in an increasing number of cases. Genomic rearrangements may position coding regions under the novel control of regulatory elements, as exemplified by the TMPRSS2-ERG fusion and the amplified enhancer identified upstream of the androgen receptor (AR) gene. Super-enhancers are increasingly found to play important roles in aberrant oncogenic transcription. Several players involved in these processes are currently being evaluated as drug targets and may represent new vulnerabilities that can be exploited for prostate cancer treatment. They include factors involved in enhancer and super-enhancer function such as bromodomain proteins and cyclin-dependent kinases. In addition, non-coding RNAs with an important gene regulatory role are being explored. The rapid progress made in understanding the influence of the non-coding part of the genome and of transcription dysregulation in prostate cancer could pave the way for the identification of novel treatment paradigms for the benefit of patients.

scholarly journals Cloning of DNA corresponding to rare transcripts of rat brain: evidence of transcriptional and post-transcriptional control and of the existence of nonpolyadenylated transcripts.

1984 ◽  
Vol 4 (10) ◽  
pp. 2187-2197 ◽  
Author(s):  
M H Brilliant ◽  
N Sueoka ◽  
D M Chikaraishi
Keyword(s):  
Rat Brain ◽  
Transcriptional Control ◽  
Cultured Cells ◽  
Cell Clone ◽  
Cell Types ◽  
Mammalian Brain ◽  
Neural Cells ◽  
Genes Encoding ◽  
Liver And Kidney ◽  
The Brain

To examine the expression of genes encoding rare transcripts in the rat brain, we have characterized genomic DNA clones corresponding to this class. In brain cells, as in all cell types, rare transcripts constitute the majority of different sequences transcribed. Moreover, when compared with other tissues or cultured cells, brain tissue may be expected to have an even larger set of rare transcripts, some of which could be restricted to subpopulations of neural cells. We have identified seven clones whose transcripts are nonabundant, averaging less than three copies per cell. Clone rg13 (rat genomic 13) RNA was detected only in the brain, whereas RNA of a second clone, rg40, was also detected in the brain and in a melanoma. Transcripts of rg13 were found in cerebellum, cerebral cortex, and regions underlying the cortex, whereas rg40 transcripts were not detected in the cerebellum. Transcripts of both rg13 and rg40 were found in pelleted polysomal RNA. RNA of another clone, rg34, was found in the brain, liver, and kidney but was found in pelleted polysomal RNA only in the brain, suggesting that its expression may be post-transcriptionally controlled. The remaining four clones represent rare transcripts that are common to the brain, liver, and kidney; rg18 RNA is restricted to the nucleus, whereas rg3, rg26, and rg36 transcripts are found in the cytoplasm of all three tissues. Transcripts of the brain-specific clone, rg13, and the commonly expressed clone, rg3, are nonpolyadenylated, presumably belonging to the high-complexity, nonpolyadenylated class of transcripts in the mammalian brain.

scholarly journals Chromatin accessibility landscapes of skin cells in systemic sclerosis nominate dendritic cells in disease pathogenesis

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Qian Liu ◽  
Lisa C. Zaba ◽  
Ansuman T. Satpathy ◽  
Michelle Longmire ◽  
Wen Zhang ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Systemic Sclerosis ◽  
Normal Skin ◽  
Cell Types ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Nucleotide Polymorphisms ◽  
Inherited Susceptibility ◽  
Unaffected Skin ◽  
Dna Regulatory Elements

AbstractSystemic sclerosis (SSc) is a disease at the intersection of autoimmunity and fibrosis. However, the epigenetic regulation and the contributions of diverse cell types to SSc remain unclear. Here we survey, using ATAC-seq, the active DNA regulatory elements of eight types of primary cells in normal skin from healthy controls, as well as clinically affected and unaffected skin from SSc patients. We find that accessible DNA elements in skin-resident dendritic cells (DCs) exhibit the highest enrichment of SSc-associated single-nucleotide polymorphisms (SNPs) and predict the degrees of skin fibrosis in patients. DCs also have the greatest disease-associated changes in chromatin accessibility and the strongest alteration of cell–cell interactions in SSc lesions. Lastly, data from an independent cohort of patients with SSc confirm a significant increase of DCs in lesioned skin. Thus, the DCs epigenome links inherited susceptibility and clinically apparent fibrosis in SSc skin, and can be an important driver of SSc pathogenesis.

scholarly journals Non-coding DNA in IBD: from sequence variation in DNA regulatory elements to novel therapeutic potential

Gut ◽  
2019 ◽  
Vol 68 (5) ◽  
pp. 928-941 ◽  
Author(s):  
Claartje Aleid Meddens ◽  
Amy Catharina Johanna van der List ◽  
Edward Eelco Salomon Nieuwenhuis ◽  
Michal Mokry
Keyword(s):  
Therapeutic Potential ◽  
Association Studies ◽  
Cell Types ◽  
Regulatory Elements ◽  
Genome Wide Association Studies ◽  
Enhancer Activity ◽  
Protein Coding ◽  
Dna Regulatory Elements ◽  
Coding Variants ◽  
Novel Therapeutic

Genome-wide association studies have identified over 200 loci associated with IBD. We and others have recently shown that, in addition to variants in protein-coding genes, the majority of the associated loci are related to DNA regulatory elements (DREs). These findings add a dimension to the already complex genetic background of IBD. In this review we summarise the existing evidence on the role of DREs in IBD. We discuss how epigenetic research can be used in candidate gene approaches that take non-coding variants into account and can help to pinpoint the essential pathways and cell types in the pathogenesis of IBD. Despite the increased level of genetic complexity, these findings can contribute to novel therapeutic options that target transcription factor binding and enhancer activity. Finally, we summarise the future directions and challenges of this emerging field.

scholarly journals Low tolerance for transcriptional variation at cohesin genes is accompanied by functional links to disease-relevant pathways

2020 ◽  
Author(s):  
William Schierding ◽  
Julia Horsfield ◽  
Justin O’Sullivan
Keyword(s):  
Regulatory Elements ◽  
Cohesin Complex ◽  
Loss Of Function ◽  
Transcriptional Variation ◽  
Genes Encoding ◽  
Full Complement ◽  
Transcriptional Changes ◽  
Matrix Production ◽  
Dna Regulatory Elements ◽  
Robust Regulation

AbstractVariants in DNA regulatory elements can alter the regulation of distant genes through spatial-regulatory connections. In humans, these spatial-regulatory connections are largely set during early development, when the cohesin complex plays an essential role in genome organisation and cell division. A full complement of the cohesin complex and its regulators is important for normal development, since heterozygous mutations in genes encoding these components are often sufficient to produce a disease phenotype. The implication that genes encoding the cohesin complex and cohesin regulators must be tightly controlled and resistant to variability in expression has not yet been formally tested. Here, we identify spatial-regulatory connections with potential to regulate expression of cohesin loci, including linking their expression to that of other genes. Connections that centre on the cohesin ring subunits (Mitotic: SMC1A, SMC3, STAG1, STAG2, RAD21/RAD21-AS; Meiotic: SMC1B, STAG3, REC8, RAD21L1), cohesin-ring support genes (NIPBL, MAU2, WAPL, PDS5A and PDS5B), and CTCF provide evidence of coordinated regulation that has little tolerance for perturbation. We identified transcriptional changes across a set of genes co-regulated with the cohesin loci that include biological pathways such as extracellular matrix production and proteasome-mediated protein degradation. Remarkably, many of the genes that are co-regulated with cohesin loci are themselves intolerant to loss-of-function. The results highlight the importance of robust regulation of cohesin genes, indicating novel pathways that may be important in the human cohesinopathy disorders.

scholarly journals Chromatin accessibility landscapes of immune cells in rheumatoid arthritis nominate monocytes in disease pathogenesis

BMC Biology ◽  
2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Dandan Zong ◽  
Beibei Huang ◽  
Young Li ◽  
Yichen Lu ◽  
Nan Xiang ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Immune Cells ◽  
Cell Types ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Systemic Autoimmune Disease ◽  
Healthy Donors ◽  
Dna Regulatory Elements

Abstract Background Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease that involves a variety of cell types. However, how the epigenetic dysregulations of peripheral immune cells contribute to the pathogenesis of RA still remains largely unclear. Results Here, we analysed the genome-wide active DNA regulatory elements of four major immune cells, namely monocytes, B cells, CD4+ T cells and CD8+ T cells, in peripheral blood of RA patients, osteoarthritis (OA) patients and healthy donors using Assay of Transposase Accessible Chromatin with sequencing (ATAC-seq). We found a strong RA-associated chromatin dysregulation signature in monocytes, but no other examined cell types. Moreover, we found that serum C-reactive protein (CRP) can induce the RA-associated chromatin dysregulation in monocytes via in vitro experiments. And the extent of this dysregulation was regulated through the transcription factor FRA2. Conclusions Together, our study revealed a CRP-induced pathogenic chromatin dysregulation signature in monocytes from RA patients and predicted the responsible signalling pathway as potential therapeutic targets for the disease.

scholarly journals DeepRegFinder: Deep Learning-Based Regulatory Elements Finder

2021 ◽  
Author(s):  
Aarthi Ramakrishnan ◽  
George Wangensteen ◽  
Sarah Kim ◽  
Eric J. Nestler ◽  
Li Shen
Keyword(s):  
Cell Types ◽  
Regulatory Elements ◽  
Related Data ◽  
Genome Wide ◽  
Genomic Scale ◽  
Multiple Cell ◽  
Model Training ◽  
Downstream Analysis ◽  
Dna Regulatory Elements ◽  
Genomic Regions

AbstractMotivationEnhancers and promoters are important classes of DNA regulatory elements that control gene expression. Identifying them at the genomic scale is a critical and challenging task in bioinformatics. The most successful method so far is to train machine learning models on known enhancer and promoter sites and predict them at other genomic regions using ChIP-seq and related data.ResultsWe have developed a highly customizable program called DeepRegFinder which automates data processing, model training and genome-wide prediction of enhancers and promoters using convolutional and recurrent neural networks. Our program further classifies the enhancers and promoters into active and poised states to facilitate downstream analysis. Based on mean average precision scores of different classes across multiple cell types, our method significantly outperforms the existing algorithms.Availabilityhttps://github.com/shenlab-sinai/DeepRegFinder

Cloning of DNA corresponding to rare transcripts of rat brain: evidence of transcriptional and post-transcriptional control and of the existence of nonpolyadenylated transcripts

1984 ◽  
Vol 4 (10) ◽  
pp. 2187-2197
Author(s):  
M H Brilliant ◽  
N Sueoka ◽  
D M Chikaraishi
Keyword(s):  
Rat Brain ◽  
Transcriptional Control ◽  
Cultured Cells ◽  
Cell Clone ◽  
Cell Types ◽  
Mammalian Brain ◽  
Neural Cells ◽  
Genes Encoding ◽  
Liver And Kidney ◽  
The Brain

To examine the expression of genes encoding rare transcripts in the rat brain, we have characterized genomic DNA clones corresponding to this class. In brain cells, as in all cell types, rare transcripts constitute the majority of different sequences transcribed. Moreover, when compared with other tissues or cultured cells, brain tissue may be expected to have an even larger set of rare transcripts, some of which could be restricted to subpopulations of neural cells. We have identified seven clones whose transcripts are nonabundant, averaging less than three copies per cell. Clone rg13 (rat genomic 13) RNA was detected only in the brain, whereas RNA of a second clone, rg40, was also detected in the brain and in a melanoma. Transcripts of rg13 were found in cerebellum, cerebral cortex, and regions underlying the cortex, whereas rg40 transcripts were not detected in the cerebellum. Transcripts of both rg13 and rg40 were found in pelleted polysomal RNA. RNA of another clone, rg34, was found in the brain, liver, and kidney but was found in pelleted polysomal RNA only in the brain, suggesting that its expression may be post-transcriptionally controlled. The remaining four clones represent rare transcripts that are common to the brain, liver, and kidney; rg18 RNA is restricted to the nucleus, whereas rg3, rg26, and rg36 transcripts are found in the cytoplasm of all three tissues. Transcripts of the brain-specific clone, rg13, and the commonly expressed clone, rg3, are nonpolyadenylated, presumably belonging to the high-complexity, nonpolyadenylated class of transcripts in the mammalian brain.

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