H3K4me3 instructs transcription at intergenic active regulatory elements [ATAC-seq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE290056 | GEO | 2025/07/17
REPOSITORIES: GEO
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Project description:Tri-methylation of lysine 4 on histone H3 (H3K4me3) is a deeply conserved and functionally important histone modification enriched at transcriptionally active promoters. H3K4me3 can facilitate RNA polymerase activity in a context-dependent manner. Here, we generated an epigenetic editing tool, dCas9-PRDM9, that efficiently deposits H3K4me3 at specific target loci, and used it to interrogate the genomic and chromatin contexts required for H3K4me3 to facilitate transcription in human cells. We found that H3K4me3 deposition is sufficient to increase transcription at active candidate cis-regulatory elements (cCREs), and that this effect was independent of cCRE identity or distance from gene promoters, unrelated to transcript levels of putative target genes, and dependent on the presence of active chromatin features. We conclude that H3K4me3 is sufficient to instruct RNA polymerase activity but requires pre-existing features of transcriptionally active chromatin. These findings suggest that disease-associated dysfunction in H3K4me3 deposition or removal can disrupt the cell’s transcriptional state.
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Project description:Tri-methylation of lysine 4 on histone H3 (H3K4me3) is a deeply conserved and functionally important histone modification enriched at transcriptionally active promoters. H3K4me3 can facilitate RNA polymerase activity in a context-dependent manner. Here, we generated an epigenetic editing tool, dCas9-PRDM9, that efficiently deposits H3K4me3 at specific target loci, and used it to interrogate the genomic and chromatin contexts required for H3K4me3 to facilitate transcription in human cells. We found that H3K4me3 deposition is sufficient to increase transcription at active candidate cis-regulatory elements (cCREs), and that this effect was independent of cCRE identity or distance from gene promoters, unrelated to transcript levels of putative target genes, and dependent on the presence of active chromatin features. We conclude that H3K4me3 is sufficient to instruct RNA polymerase activity but requires pre-existing features of transcriptionally active chromatin. These findings suggest that disease-associated dysfunction in H3K4me3 deposition or removal can disrupt the cell’s transcriptional state.
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Project description:Tri-methylation of lysine 4 on histone H3 (H3K4me3) is a deeply conserved and functionally important histone modification enriched at transcriptionally active promoters. H3K4me3 can facilitate RNA polymerase activity in a context-dependent manner. Here, we generated an epigenetic editing tool, dCas9-PRDM9, that efficiently deposits H3K4me3 at specific target loci, and used it to interrogate the genomic and chromatin contexts required for H3K4me3 to facilitate transcription in human cells. We found that H3K4me3 deposition is sufficient to increase transcription at active candidate cis-regulatory elements (cCREs), and that this effect was independent of cCRE identity or distance from gene promoters, unrelated to transcript levels of putative target genes, and dependent on the presence of active chromatin features. We conclude that H3K4me3 is sufficient to instruct RNA polymerase activity but requires pre-existing features of transcriptionally active chromatin. These findings suggest that disease-associated dysfunction in H3K4me3 deposition or removal can disrupt the cell’s transcriptional state.
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Project description:Misregulated gene expression in human hearts can result in cardiovascular diseases that are leading causes of morbidity and mortality worldwide. However, the limited information on the genomic location of candidate cis-regulatory elements (cCRE) such as enhancers and promoters in distinct cardiac cell types has restricted the understanding of these diseases. Here, we defined >287,000 cCREs in the four chambers of the human heart at single-cell resolution, which revealed cCREs and candidate transcription factors associated with cardiac cell types in a region-dependent manner and during heart failure. We further discovered cardiovascular disease-associated genetic variants enriched within these cCREs including 38 candidate causal atrial fibrillation variants localized to cardiomyocyte cCREs. Additional functional studies revealed that two of these variants affect a cCRE controlling KCNH2/HERG expression and action potential repolarization. Overall, this comprehensive atlas of human cardiac cCREs provides the foundation for illuminating cell type-specific gene regulation in human hearts during health and disease.
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Project description:Misregulated gene expression in human hearts can result in cardiovascular diseases that are leading causes of morbidity and mortality worldwide. However, the limited information on the genomic location of candidate cis-regulatory elements (cCRE) such as enhancers and promoters in distinct cardiac cell types has restricted the understanding of these diseases. Here, we defined >287,000 cCREs in the four chambers of the human heart at single-cell resolution, which revealed cCREs and candidate transcription factors associated with cardiac cell types in a region-dependent manner and during heart failure. We further discovered cardiovascular disease-associated genetic variants enriched within these cCREs including 38 candidate causal atrial fibrillation variants localized to cardiomyocyte cCREs. Additional functional studies revealed that two of these variants affect a cCRE controlling KCNH2/HERG expression and action potential repolarization. Overall, this comprehensive atlas of human cardiac cCREs provides the foundation for illuminating cell type-specific gene regulation in human hearts during health and disease.
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