Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA316990 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR3317030_1.fastq.gz | Fastqsanger.gz | |||
| SRR3317030_2.fastq.gz | Fastqsanger.gz | |||
| SRR3317031_1.fastq.gz | Fastqsanger.gz | |||
| SRR3317031_2.fastq.gz | Fastqsanger.gz | |||
| SRR3317023_1.fastq.gz | Fastqsanger.gz |
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Project description:HLA-G is a nonclassical HLA molecule expressed specifically in the placenta. While it is known to play a central role in maternal immune tolerance during pregnancy, the mechanism underlying its tissue-specific expression remains poorly understood. To elucidate this mechanism, we used a Massively Parallel Reporter Assay (MPRA) to systematically interrogate the HLA-G locus. This uncovered Enhancer L, a novel cis-regulatory element with enhancer activity 12kb upstream of HLA-G. To verify enhancer function and specificity for HLA-G in culture, we deleted Enhancer L in JEG3 cells and performed RNA sequencing and differential expression analysis. Upon Enhancer L knockout, we observe complete ablation of HLA-G and minimal dysregulation of other genes within 2Mb, suggesting that HLA-G is the only direct cis target of Enhancer L. DNase-seq and Chromatin Conformation Capture (3C) confirm that Enhancer L is a cell type-specific enhancer that loops into the HLA-G promoter. MPRA-based saturation mutagenesis of Enhancer L identifies motifs for transcription factors of the CEBP and GATA families which are essential for placentation. These factors associate with Enhancer L and regulate HLA-G expression. Our findings identify long-range chromatin looping mediated by core trophoblast transcription factors as a novel mechanism controlling tissue-specific HLA-G expression at the maternal-fetal interface.
2016-05-05 | GSE79779 | GEO
Project description:HLA-C arose during evolution of pregnancy in the Great Apes 10-15 million years ago. It has a dual function on placental extravillous trophoblasts (EVT) as it contributes to both tolerance and immunity at the maternal-fetal interface. The mode of its regulation is of considerable interest in connection with the biology of pregnancy and pregnancy abnormalities. First trimester primary EVT in which HLA-C is highly expressed, as well as JEG3, an EVT model cell lines, were employed. Single cell RNA-seq data and quantitative PCR identified high expression of the transcription factor ELF3 in those cells. ChIP-PCR confirmed that both ELF3 and MED1 bound to the proximal HLA-C promoter region. However, binding of RFX5 to this region was absent or severely reduced and the adjacent HLA-B locus remained closed. Expression of HLA-C was inhibited by ELF3 siRNAs and by wrenchnolol treatment. Wrenchnolol is a cell-permeable synthetic organic molecule that mimics ELF3 and is relatively specific for binding to ELF3’s coactivator, MED23, as our data also showed in JEG3. Moreover, the ELF3 gene is regulated by a super-enhancer that spans more than 5 Mb, identified by ATAC-seq, as well as by its sensitivity to (+)-JQ1 (inhibitor of BRD4). ELF3 bound to its own promoter, thus creating an autoregulatory feedback loop that establishes expression of ELF3 and HLA-C in trophoblasts. Wrenchnolol blocked binding of MED23 to ELF3, thus disrupting the positive feedback loop that drives ELF3 expression, with down regulation of HLA-C expression as a consequence.
2021-01-27 | GSE165511 | GEO
Project description:Cyclin Dependent Kinases CDK8 and CDK19 (Mediator kinase) are regulatory components of the Mediator complex, a highly conserved complex that fine tunes transcriptional output. While Mediator kinase has been implicated in the transcriptional control of key pathways necessary for development and growth, its function in vivo has not been well described. Herein, we report the consequences of complete ablation of both Cdk8/19 on tissue homeostasis. We show that intestinal epithelial specific deletion of Mediator kinase leads to a distinct defect in secretory progenitor differentiation with broad loss of the intestinal secretory cell types. Using a phospho-proteogenomic approach, we show that the Cdk8/19 kinase module interacts with and phosphorylates components of the chromatin remodeling complex Swi/Snf in intestinal epithelial cells. Genomic localisation of Swi/Snf and Mediator shows Cdk8/19-dependent genomic binding at distinct super-enhancer loci within key lineage specification genes, including the master regulator of secretory differentiation ATOH1. Using CRISPRi/CRISPRa, we identify a distinct Mediator-Swi/Snf bound enhancer element that is necessary and sufficient for ATOH1 expression in a Mediator-kinase dependent manner. As such, these studies uncover a newly described transcriptional mechanism of ATOH1-dependent intestinal cell specification that is dependent on the coordinated interaction of the chromatin remodeling complex Swi/Snf and Mediator complex.
2023-03-11 | PXD030256 | Pride
Project description:Cyclin Dependent Kinases CDK8 and CDK19 (Mediator kinase) are regulatory components of the Mediator complex, a highly conserved complex that fine tunes transcriptional output. While Mediator kinase has been implicated in the transcriptional control of key pathways necessary for development and growth, its function in vivo has not been well described. Herein, we report the consequences of complete ablation of both Cdk8/19 on tissue homeostasis. We show that intestinal epithelial specific deletion of Mediator kinase leads to a distinct defect in secretory progenitor differentiation with broad loss of the intestinal secretory cell types. Using a phospho-proteogenomic approach, we show that the Cdk8/19 kinase module interacts with and phosphorylates components of the chromatin remodeling complex Swi/Snf in intestinal epithelial cells. Genomic localisation of Swi/Snf and Mediator shows Cdk8/19-dependent genomic binding at distinct super-enhancer loci within key lineage specification genes, including the master regulator of secretory differentiation ATOH1. Using CRISPRi/CRISPRa, we identify a distinct Mediator- Swi/Snf bound enhancer element that is necessary and sufficient for ATOH1 expression in a Mediator-kinase dependent manner. As such, these studies uncover a newly described transcriptional mechanism of ATOH1-dependent intestinal cell specification that is dependent on the coordinated interaction of the chromatin remodeling complex Swi/Snf and Mediator complex.
2023-03-10 | PXD030212 | Pride
Project description:Transcriptional profiling of human mesenchymal stem cells comparing normoxic MSCs cells with hypoxic MSCs cells. Hypoxia may inhibit senescence of MSCs during expansion. Goal was to determine the effects of hypoxia on global MSCs gene expression.
2011-02-19 | GSE20463 | GEO
Project description:Transcriptional profiling of human mesenchymal stem cells comparing normoxic MSCs cells with hypoxic MSCs cells. Hypoxia may inhibit senescence of MSCs during expansion. Goal was to determine the effects of hypoxia on global MSCs gene expression. Two-condition experiment, Normoxic MSCs vs. Hypoxic MSCs.
2011-02-19 | E-GEOD-20463 | biostudies-arrayexpress
Project description:Receptors for estrogen and progesterone frequently interact, via Cohesin/CTCF loop extrusion, at enhancers distal from regulated genes; CTCF is decreased or mutated in >20% of human endometrial tumors, indicating its importance in uterine homeostasis. To better understand how CTCF-mediated enhancer-gene interactions impact endometrial development and function, the Ctcf gene was selectively deleted in female reproductive tissues of mice. Prepubertal Ctcfd/d uterine tissue exhibited normal morphology, with a significant reduction in the number of uterine glands compared to those without Ctcf deletion (Ctcff/f mice). Post-pubertal Ctcfd/d uteri were hypoplastic with significant reduction in both the size of the endometrial stroma and number of glands. Transcriptional profiling revealed increased expression of stem cell molecules Lif, EOMES and Lgr5, and enhanced inflammation pathways following Ctcf deletion. Analysis of the response of the uterus to steroid hormone stimulation showed that the response of the uterus to estrogen was not impacted, but that CTCF deletion affects a subset of progesterone responsive genes. This finding indicates 1) mediators of P signaling remain functional following Ctcf deletion and 2) certain P regulated genes are sensitive to Ctcf deletion, suggesting they depend on gene-enhancer interactions that require CTCF. The P responsive genes altered by CTCF ablation included Ihh, Fst and Errfi1, as well as other genes involved in the regulation of critical processes including hormone response, transcription, and inhibition of tumor generation. Overall, our findings reveal that uterine Ctcf plays a key role in P dependent expression of uterine genes underlying optimal post pubertal uterine development.
2024-08-08 | GSE227517 | GEO
Project description:Receptors for estrogen and progesterone frequently interact, via Cohesin/CTCF loop extrusion, at enhancers distal from regulated genes; CTCF is decreased or mutated in >20% of human endometrial tumors, indicating its importance in uterine homeostasis. To better understand how CTCF-mediated enhancer-gene interactions impact endometrial development and function, the Ctcf gene was selectively deleted in female reproductive tissues of mice. Prepubertal Ctcfd/d uterine tissue exhibited normal morphology, with a significant reduction in the number of uterine glands compared to those without Ctcf deletion (Ctcff/f mice). Post-pubertal Ctcfd/d uteri were hypoplastic with significant reduction in both the size of the endometrial stroma and number of glands. Transcriptional profiling revealed increased expression of stem cell molecules Lif, EOMES and Lgr5, and enhanced inflammation pathways following Ctcf deletion. Analysis of the response of the uterus to steroid hormone stimulation showed that the response of the uterus to estrogen was not impacted, but that CTCF deletion affects a subset of progesterone responsive genes. This finding indicates 1) mediators of P signaling remain functional following Ctcf deletion and 2) certain P regulated genes are sensitive to Ctcf deletion, suggesting they depend on gene-enhancer interactions that require CTCF. The P responsive genes altered by CTCF ablation included Ihh, Fst and Errfi1, as well as other genes involved in the regulation of critical processes including hormone response, transcription, and inhibition of tumor generation. Overall, our findings reveal that uterine Ctcf plays a key role in P dependent expression of uterine genes underlying optimal post pubertal uterine development.
2024-08-08 | GSE227519 | GEO
Project description:Both genetic and environmental factors are implicated in Type 1 Diabetes (T1D). Since environmental factors can trigger epigenetic changes, we hypothesized that variations in histone posttranslational modifications (PTMs) at the promoter/enhancer regions of T1D susceptible genes may be associated with T1D. We therefore evaluated histone PTM variations at known T1D susceptible genes in blood cells from T1D patients versus healthy non-diabetic controls, and explored their connections to T1D. We used the chromatin-immunoprecipitation-linked-to-microarray approach to profile key histone PTMs, including H3-lysine-4 trimethylation (H3K4me3), H3K27me3, H3K9me3, H3K9 acetylation (H3K9Ac) and H4K16Ac at genes within the T1D susceptible loci in lymphocytes, and H3K4me3, H3K9me2, H3K9Ac and H4K16Ac at the IDDM1 region in monocytes of T1D patients and healthy controls separately. We screened for potential variations in histone PTMs using computational methods to compare datasets from T1D and controls. Interestingly, we observed marked variations in H3K9Ac levels at the upstream regions of HLA-DRB1 and HLA-DQB1 within the IDDM1 locus in T1D monocytes relative to controls. Additional experiments with THP-1 monocytes demonstrated increased expression of HLA-DRB1 and HLA-DQB1 in response to interferon- and TNF-treatment that were accompanied by changes in H3K9Ac at the same promoter regions as that seen in the patient monocytes. These results suggest that the H3K9Ac status of HLA-DRB1 and HLA-DQB1, two genes highly associated with T1D, may be relevant to their regulation and transcriptional response towards external stimuli. Thus, the promoter/enhancer architecture and chromatin status of key susceptible loci could be important determinants in their functional association to T1D susceptibility. We used microarrays to obtain global gene expression data in human lymphocytes. Human lymphocytes were prepared from four healthy non-diabetic volunteers. Total RNAs were extracted using Qiagen RNeasy mini kits following the manufacturer's instructions. Biotinylated single-strand cDNA was generated and subjected to expression profiling with Affymetrix Human Gene 1.0 ST arrays, followed by data analyses and conversion into expression measurements using Affymetrix's Expression Console v1.1.1. The data set is used for integration with ChIP array data.
2012-05-31 | E-GEOD-36084 | biostudies-arrayexpress