Enhancers with tissue-specific activity are enriched in intronic regions
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB45744 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR6066810.fastq.gz | Fastqsanger.gz | |||
| ERR6066820.fastq.gz | Fastqsanger.gz | |||
| ERR6066811.fastq.gz | Fastqsanger.gz | |||
| ERR6066821.fastq.gz | Fastqsanger.gz | |||
| ERR6066812.fastq.gz | Fastqsanger.gz |
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Project description:We have performed ChIP-seq of H3K27ac and H3K4me3 histone post-translational modifications at three stages during induced neural differentiation (ESCs, neural progenitors and neurons). This data has allowed us to identify candidate enhancer-like signatures in the genome, which we have defined as regions that are enriched in H3K27ac and depleted of H3K4me3.
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Project description:Tissue function and homeostasis reflect the gene expression signature by which the combination of ubiquitous and tissue-specific genes contribute to the tissue maintenance and stimuli-responsive function. Enhancers are central to control this tissue-specific gene expression pattern. Here, we explore the correlation between the genomic location of enhancers and their role in tissue-specific gene expression. We find that enhancers showing tissue-specific activity are highly enriched in intronic regions and regulate the expression of genes involved in tissue-specific functions, whereas housekeeping genes are more often controlled by intergenic enhancers, common to many tissues. Notably, an intergenic-to-intronic active enhancers continuum is observed in the transition from developmental to adult stages: the most differentiated tissues present higher rates of intronic enhancers, whereas the lowest rates are observed in embryonic stem cells. Altogether, our results suggest that the genomic location of active enhancers is key for the tissue-specific control of gene expression.
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Project description:Determining the spatial and temporal activity patterns of enhancers remains a challenge in the functional annotation of the human genome. Here, we performed genome-wide mapping of tissue-specific in vivo binding sites for the enhancer-associated protein p300 and assessed in transgenic mice the utility of this information in identifying enhancers and predicting their activity patterns. Chromatin immunoprecipitation followed by massively-parallel sequencing was used to identify p300-enriched sites in mouse embryonic day 11.5 (e11.5) forebrain, midbrain, and limb. In total, 4,686 genomic regions were enriched for p300 in vivo in at least one of these tissues. To determine whether p300-binding accurately identifies enhancers and predicts their activity patterns, we tested 86 of these regions in a transgenic mouse enhancer assay at e11.5. In 88% of the cases, p300-enriched sequences were reproducible enhancers, and in 91% of these cases p300 enrichment correctly predicted the tissues in which in vivo activity was observed. Our results indicate that in vivo mapping of p300 binding to non-coding DNA is a highly effective means for identifying enhancers and their associated spatial activity patterns. Examination of p300 binding in 3 embryonic stage 11.5 mouse tissues
2009-02-11 | E-GEOD-13845 | biostudies-arrayexpress
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:Determining the spatial and temporal activity patterns of enhancers remains a challenge in the functional annotation of the human genome. Here, we performed genome-wide mapping of tissue-specific in vivo binding sites for the enhancer-associated protein p300 and assessed in transgenic mice the utility of this information in identifying enhancers and predicting their activity patterns. Chromatin immunoprecipitation followed by massively-parallel sequencing was used to identify p300-enriched sites in mouse embryonic day 11.5 (e11.5) forebrain, midbrain, and limb. In total, 4,686 genomic regions were enriched for p300 in vivo in at least one of these tissues. To determine whether p300-binding accurately identifies enhancers and predicts their activity patterns, we tested 86 of these regions in a transgenic mouse enhancer assay at e11.5. In 88% of the cases, p300-enriched sequences were reproducible enhancers, and in 91% of these cases p300 enrichment correctly predicted the tissues in which in vivo activity was observed. Our results indicate that in vivo mapping of p300 binding to non-coding DNA is a highly effective means for identifying enhancers and their associated spatial activity patterns.
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Project description:Chromosomal translocations in non-Hodgkin lymphoma (NHL) are known to bring oncogenes (e.g. MYC, BCL2) under the regulation of immunoglobulin heavy chain (IGH) super-enhancers, composed of the intronic Eµ enhancer and 3’ regulatory regions (3’RR1, 3’RR2). Deregulation of translocated oncogenes by enhancer activity can contribute to lymphomagenesis. The role of IGH enhancers in normal B-cell development is well established, but the knowledge regarding precise mechanisms of their involvement in control of the translocated oncogenes is limited. We previously identified exact regions within IGH regulatory elements, one in the Eµ and two in each of the 3'RRs, whose targeting profoundly inhibited NHL cells growth. The goal of this project was to reveal enhancer RNAs (eRNA) transcribed from Eµ and 3'RRs and their essential regions. With the use of chromatin-enriched RNA-Seq we confirmed bi-directional transcription from those core enhancer regions and further validated eRNAs expression in a large panel of NHL cell lines and in patient-derived samples. We showed in several NHL cell lines that CRISPR/dCas9-KRAB-mediated inhibition of essential IGH enhancer regions decreased expression of eRNAs and translocated oncogenes in the fashion likely related to their breakpoints pattern within IGH locus. Our results provide new insights into the current understanding of IGH enhancers role in B-cell NHLs.
2024-06-10 | GSE247393 | GEO
Project description:Experience-dependent gene transcription is required for nervous system development and function. However, the DNA regulatory elements that control this program of gene expression are not well defined. Here we characterize the enhancers that function across the genome to mediate activity-dependent transcription in neurons. While ~12,000 putative activity-regulated enhancer sequences have previously been identified that are enriched for H3K4me1 and the histone acetyltransferase CBP, we find that this chromatin signature is not sufficient to distinguish which of these regulatory sequences are actively engaged in promoting activity-dependent transcription. We show here that a subset of H3K4me1/CBP positive enhancers that is enriched for H3K27 acetylation (H3K27ac) in vivo, and shows increased H3K27ac upon membrane depolarization of cortical neurons, function to regulate activity-dependent transcription. The function of many of these activity-regulated enhancers appears to be dependent on the binding of FOS, a protein that had previously been thought to interact primarily with the promoters of activity-regulated genes. Furthermore, many of these target genes in cortical neurons encode neuron specific proteins that regulate synaptic development and function. These findings suggest that FOS functions at enhancers to control activity-dependent gene programs that are critical for nervous system function, and provide a resource of activity-dependent enhancers that may give insight into genetic variation that contributes to brain development and disease. Genome-wide maps of H3K27ac and AP1 transcription factors (CFOS, FOSB, JUNB) before and after neuronal activity in mouse cortical neurons.
2014-09-07 | E-GEOD-60192 | biostudies-arrayexpress
Project description:Background and Purpose: We previously showed that intracranial aneurysm (IA)-associated single nucleotide polymorphisms (SNPs) are enriched in promoters and putative enhancers of the human circle of Willis (CoW), on which IAs develop, suggesting a role for such regulatory regions in IA. In this study we further investigated the role of these putative enhancers in the pathogenesis of IA by identifying the target genes of these enhancers and validating their regulatory activity. Methods: We selected putative enhancers in IA-associated regions from genome wide association studies, using our previously published CoW chromatin immunoprecipitation and sequencing data. Next, we used a chromatin conformation capture technique (4C) to identify physical interactions between these putative enhancers and the promoters of their target genes. Subsequently, we assessed the activity of the identified enhancers in vivo in zebrafish embryos and we analyzed gene expression of the target genes identified with 4C in CoW RNA-sequencing data and by in situ hybridization on CoW paraffin sections. Results: We identified fifteen enhancers that interact with the promoters of six target genes: SOX17, CDKN2B, MTAP, CNNM2, RPEL1 and GATA6. For eight out of eleven enhancers that could be tested, we confirmed in vivo activity in the zebrafish embryos. These eight enhancers reside in four out of six IA-associated GWAS regions. All six target genes are expressed in the CoW and in situ hybrdization showed that these genes are expressed in multiple cell types in the CoW. Conclusions: In four out of six IA-associated GWAS regions we identified eight enhancers that are active in vivo and interact with six nearby genes, suggesting that these genes are regulated by the identified enhancers. These genes, SOX17, CDKN2B, MTAP, CNNM2, RPEL1 and GATA6, are potential candidate genes involved in IA pathogenesis and should be studied using animal models in the future.
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Project description:We anticipated that the identification of cis-regulatory regions active in pancreatic islets would help increase our understanding of islet biology and the pathology of diabetes. Towards this end we used histone H3 lysine 4 monomethylation-based nucleosome predictions genome-wide, in conjunction with binding data for PDX1, FOXA2, MAFA, and NEUROD1, to identify 3,654 putative enhancers that are H3K4me1-enriched uniquely in islets as compared to 14 other tissue or cell-types. We show that these islet-specific enhancers are associated with genes with significantly higher islet specificity than genes associated with non-specific enhancers. Further, islet-specific enhancers were not enriched for typical active or repressive histone methylations in embryonic stem cells and liver, suggesting they are formed by de novo histone methylation during pancreas development. We also identify a subset of enhancers bivalently marked by both H3K4me1 and H3K27me3 in adult pancreatic islets. Further, we show that islet-specific enhancers triple- or quadruple- bound by PDX1, MAFA, NEUROD1 and/or FOXA2 are associated with genes with particularly high islet-specificity, and that these loci are enriched in regions with functional activity in islet cell types. Finally, we demonstrate that cytokines reduce H3K4me1 enrichment levels at selected triple- or quadruple-bound islet-specific enhancers, suggesting that epigenetic changes may contribute to cytokine-induced b-cell dysfunction. In conjunction with data from Hoffman et al Genome Research 2010, an analysis of histone modifications and transcription factor binding sites to identify enhancer regions
2011-06-30 | E-GEOD-30298 | biostudies-arrayexpress
Project description:We used genome-wide sequencing methods to study stimulus-dependent enhancer function in neurons. We identified ~12,000 neuronal activity-regulated enhancers that are bound by the general transcriptional co-activator CBP in an activity-dependent manner. A function of CBP at enhancers may be to recruit RNA polymerase II (RNAPII), as we also observed activity-regulated RNAPII binding to thousands of enhancers. Remarkably, RNAPII at enhancers transcribes bi-directionally a novel class of enhancer RNAs (eRNAs) within enhancer domains defined by the presence of histone H3 that is mono-methylated at lysine 4 (H3K4me1). The level of eRNA expression at neuronal enhancers positively correlates with the level of mRNA synthesis at nearby genes, suggesting that eRNA synthesis occurs specifically at enhancers that are actively engaged in promoting mRNA synthesis. These findings reveal that a widespread mechanism of enhancer activation involves RNAPII binding and eRNA synthesis. Examination of genome-wide binding of three types of modified histones, four transcription factors, and RNA polymerase II (ChIP-Seq), as well as RNA expression (RNA-Seq) before and after membrane depolarization via application of extracellular potassium.
2010-04-14 | E-GEOD-21161 | biostudies-arrayexpress