Nascent transcriptome in T-ALL bone marrow
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ABSTRACT:
PROVIDER: EGAS00001005864 | EGA |
REPOSITORIES: EGA
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Project description:Cell fate transitions are accompanied by global transcriptional, epigenetic and topological changes driven by transcription factors (TFs), as is strikingly exemplified by reprogramming somatic cells to pluripotent stem cells (PSCs) via expression of OCT4, KLF4, SOX2 and cMYC. How TFs orchestrate the complex molecular changes around their target gene loci in a temporal manner remains incompletely understood. Here, using KLF4 as a paradigm, we provide the first TF-centric view of chromatin reorganization and its association to 3D enhancer rewiring and transcriptional changes of linked genes during reprogramming of mouse embryonic fibroblasts (MEFs) to PSCs. Inducible depletion of KLF factors in PSCs caused a genome-wide decrease in the connectivity of enhancers, while disruption of individual KLF4 binding sites from PSC-specific enhancers was sufficient to impair enhancer-promoter contacts and reduce expression of associated genes. Our study provides an integrative view of the complex activities of a lineage-specifying TF during a controlled cell fate transition and offers novel insights into the order and nature of molecular events that follow TF binding.
2019-09-03 | PXD014631 | Pride
Project description:The transition of pluripotent stem cells (PSCs) from primed to naïve states constitutes a prototypical example of cellular plasticity. The naïve state can be stabilized by defined chemical cocktails that block extracellular signals, notably including the MEK pathway. However, little is known regarding the underlying transcriptional mechanisms. Here, we report that the transcriptional landscape of the naïve state can be mimicked in mouse and human PSCs by stimulating transcriptional enhancers. This is attained by inhibiting the CDK8 and CDK19 kinases, which are negative regulators of Mediator, a critical component of enhancer function. Mechanistically, CDK8/19i triggers a global increase in the recruitment of RNA Pol II at promoters and enhancers, hyperactivating enhancers and their target genes. Lastly, the emergence of naïve pluripotency in the pre-implantation epiblast coincides with a marked reduction in CDK8/19 activity, and CDK8/19i blocks its subsequent developmental progression. These findings suggest that naïve pluripotency during development includes hyperactivation of enhancers and can be captured in vitro, either by blunting extracellular signaling, or by stimulating enhancer-driven transcription. These principles may apply to other cellular transitions.
2020-09-29 | PXD009200 | Pride
Project description:We applied a global approach using broad-range, next-generation sequecing to identify a repertoire of eosinophil-specific enhancers. H3K4me1, H3K4me3, H3K27ac and PU.1 ChIPseq data was paired with ATAC and gene expression data from bmEos. Transcription factor motif analysis revealed enrichment for PU.1 in eosinophil enhancers, and ChIP-seq confirmed PU.1 binding in enhancer of genes highly expressed in eosinophils. Comparison of identified PU.1-bound enhancers with 3 publically available myeloid datasets (neutrophils, bone marrow derived macrophages and immature granulocytes) revealed 25% of PU.1-bound enhancers were unique to eosinophils - an eosinophil-specific PU.1 regulome. GO analysis of eosinophil-specific PU.1-bound enhancers revealed enrichmend for genes involved in migration, proliferation, degranulation and survival. Collectively, our data identify eosinophil-specific enhancers regulating key eosinophil genes through epigenetic mechanisms and TF binding. These findings are supportive of a dynamic, epigenetic eosinophil regulome underlying eosinophil function and diversity.
2021-06-08 | GSE144951 | GEO
Project description:We sequenced Chromatin-bound RNA (also known as ChromRNA-seq) to measure the transcriptional activity at enhancers.
2020-08-01 | GSE145017 | GEO
Project description:The integrated activity of cis-regulatory elements fine-tunes transcriptional programs of mammalian cells by recruiting cell type–specific as well as ubiquitous transcription factors (TFs). Despite their key role in modulating transcription, enhancers are still poorly characterized at the molecular level, and their limited DNA sequence conservation in evolution and variable distance from target genes make their unbiased identification challenging. The coexistence of high mono-methylation and low tri-methylation levels of lysine 4 of histone H3 is considered a signature of enhancers, but a comprehensive view of histone modifications associated to enhancers is still lacking. By combining chromatin immunoprecipitation (ChIP) with mass spectrometry, we investigated cis-regulatory regions in macrophages to comprehensively identify histone marks specifically associated with enhancers, and to profile their dynamics after transcriptional activation elicited by an inflammatory stimulation. The intersection of the proteomics data with ChIP-seq and RNA-seq analyses revealed the existence of novel subpopulations of enhancers, marked by specific histone modification signatures: specifically, H3K36me2/K4me1 marks transcribed enhancers, while H3K36me3/K4me1 and H3K79me2/K4me1 combinations mark distinct classes of intronic enhancers. Thus, our MS analysis of functionally distinct genomic regions revealed the combinatorial code of histone modifications, highlighting the potential of proteomics in addressing fundamental questions in epigenetics.
2017-10-09 | PXD007582 | Pride
Project description:Mediator complex regulates transcription by connecting enhancers to promoters. High Mediator binding density defines super enhancers, which regulate cell-identity genes and oncogenes. Protein interactions of Mediator may explain its role in these processes but have not been identified comprehensively. Here we purify Mediator from neural stem cells (NSCs) and identify 75 protein-protein interaction partners. We identify super enhancers in NSCs and show that Mediator-interacting chromatin modifiers colocalise with Mediator at enhancers and super enhancers. Transcription factor families with high affinity for Mediator dominate enhancers and super enhancers and can explain genome-wide Mediator localization. We identify E-box transcription factor Tcf4 as a key regulator of NSCs. Tcf4 interacts with Mediator, colocalises with Mediator at super enhancers and regulates neurogenic transcription factor genes with super enhancers and broad H3K4me3 domains. Our data suggest that high binding-affinity for Mediator is an important organizing feature in the transcriptional network that determines NSC identity.
2019-05-06 | PXD013546 | Pride
Project description:During development and differentiation, enhancers, and not promoters are most dynamic in their DNA methylation status. However, the causal relationship between enhancer activity and methylation is not clear. Here, we describe that during early zebrafish development, enhancer activity has little influence on DNA methylation, and that hypo-methylation is a unique feature of primed enhancers, whereas active enhancers are hyper-methylated. Hypo-methylated enhancers (hypo-enhancers) are enriched close to important transcription factors (TFs) that act later in development, are specifically de-methylated before the maternal-zygotic transition (MZT), and reside in a unique epigenetic environment. Finally, we demonstrate that hypo-enhancers are functionally active and that they are physically associated with the transcriptional start site (TSS) of target-genes, irrespective of target-gene activity. In conclusion, we demonstrate that early development in zebrafish represents a time-window characterized by non-canonical DNA methylation-enhancer relationships, including global DNA hypo-methylation of inactive enhancers and DNA hyper-methylation of active enhancers. DNA methylation profiles of 4 time points during zebrafish early development.
2015-11-09 | E-GEOD-74789 | biostudies-arrayexpress
Project description:Hox genes are required for the development of the intestinal caecum, a major organ of species eating plants. We have analysed the transcriptional regulation of Hoxd genes in caecal buds and show that they are controlled by a series of enhancers located in a gene desert telomeric to the HoxD cluster. The start site of two neighboring and opposite long non-coding RNAs, Hotdog and Twin of Hotdog, specifically transcribed in the caecum, contacts the expressed Hoxd genes in the framework of a topological domain, a large domain of interactions, which ensures a robust transcription of these genes during caecum budding. We show that hedgehogs have kept this regulatory potential despite the absence of caecum, suggesting that these enhancers are used in other developmental situations. In this context, we discuss some striking similarities between the caecum and the limb buds, suggesting the implementation of a common budding tool-kit. Transcriptional activity at the HoxD locus in developing caeca at E13.5 Transcriptional activity at the HoxD locus in developing caeca at E13.5
2013-10-23 | E-GEOD-44367 | biostudies-arrayexpress
Project description:Widespread transcription at neuronal activity-regulated enhancers
| PRJNA126613 | ENA
Project description:T cells are known to develop in the thymus. However, molecular events that control the transition from hematopoietic progenitor cells in the bone marrow to T precursor cells seeded in the thymus remained poorly defined. Our recent report showed that osteocalcin (Ocn)-expressing bone cells in the bone marrow have major impact on T cell immunity by regulating T progenitor development in the bone marrow (Yu et al., 2015) [1]. Selective endogenous depletion of Ocn(+) cells by inducible diphtheria toxin receptor expression (OcnCre;iDTR) led to reduction of T-competent common lymphoid progenitors (Ly6D(-) CLPs) in the bone marrow and loss of T cells in the thymus. Expression of the Notch ligand DLL4 by Ocn(+) cells in the bone marrow ensures the production of Ly6D(-) CLPs, and expression of chemotactic molecules CCR7 and PSGL1 to enable subsequent thymic seeding. These data indicate that specific mesenchymal cells in bone marrow provide key molecular drivers enforcing thymus-seeding progenitor generation and thereby directly link skeletal biology to the production of T cell based adaptive immunity. Here we present the transcriptome profiles of Ly6D(-) CLPs derived from Ocn(+) cells deleted mice (OcnCre(+);iDTR) compared to those derived from control littermates (OcnCre(-);iDTR). These data are publically available from NCBI Gene Expression Omnibus (GEO) with the accession number GSE66102.
| S-EPMC4583637 | biostudies-literature