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Genome-wide analysis of enhancer landscape in colorectal cancer subgroups (RNA-seq)

ABSTRACT: Colorectal cancer (CRC) is a highly malignant solid tumor and causes millions of cancer related death worldwide. Here, using H3K27ac chromatin immunoprecipitation followed by sequencing (ChIP-seq) coupled with gene expression data (RNA-seq), we describe the active cis-regulatory landscape across more than seventy diverse CRC patient tissues, including tumor and native tissue. Analysis of the enhancers and super-enhancers with recurrently gained or lost activity revealed novel, clinically relevant insights into CRC biology. Computational reconstruction of core regulatory circuitry identified a master set of transcription factors which is responsible for tumorigenesis and the maintenance of normal intestinal function. Genomic studies have revealed four distinct consensus molecular subgroups (CMS) with divergent biology and clinical behavior and we reveal that differentially regulated enhancers and super-enhancers reinforced inter-subgroup heterogeneity. Our integrated analysis of enhancer elements in a large series of CRC patient paired samples reveals novel insights into cis-regulatory architecture, unrecognized dependencies, and cellular origins.

ORGANISM(S): Homo sapiens

PROVIDER: GSE156451 | GEO | 2021/08/26

REPOSITORIES: GEO

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Genome-wide analysis of enhancer landscape in colorectal cancer subgroups (ChIP-seq)

Project description:Colorectal cancer (CRC) is a highly malignant solid tumor and causes millions of cancer related death worldwide. Here, using H3K27ac chromatin immunoprecipitation followed by sequencing (ChIP-seq) coupled with gene expression data (RNA-seq), we describe the active cis-regulatory landscape across more than seventy diverse CRC patient tissues, including tumor and native tissue. Analysis of the enhancers and super-enhancers with recurrently gained or lost activity revealed novel, clinically relevant insights into CRC biology. Computational reconstruction of core regulatory circuitry identified a master set of transcription factors which is responsible for tumorigenesis and the maintenance of normal intestinal function. Genomic studies have revealed four distinct consensus molecular subgroups (CMS) with divergent biology and clinical behavior and we reveal that differentially regulated enhancers and super-enhancers reinforced inter-subgroup heterogeneity. Our integrated analysis of enhancer elements in a large series of CRC patient paired samples reveals novel insights into cis-regulatory architecture, unrecognized dependencies, and cellular origins.

2021-08-26 | GSE156613 | GEO

Transcriptional super-enhancers connected to cell identity and disease

Project description:Super-enhancers are large clusters of transcriptional enhancers that drive expression of genes that control and define cell identity. Improved understanding of the roles super-enhancers play in biology would be afforded by knowing the constellation of factors that constitute these domains and by identifying super-enhancers across the spectrum of human cell types. We describe here the population of transcription factors, cofactors, chromatin regulators and core transcription apparatus that occupy super-enhancers in embryonic stem cells (ESCs) and evidence that super-enhancers are highly transcribed. We then use epigenomic data to produce a catalogue of super-enhancers in a broad range of human cell types. These super-enhancer domains are associated with genes encoding master transcription factors and other components that play important roles in the biology of these cells. Interestingly, sequence variation associated with a broad spectrum of diseases is especially enriched in the super-enhancers of disease-relevant cell types. Furthermore, we find that cancer cells generate super-enhancers at oncogenes and other genes that play important roles in tumor pathogenesis. We discuss these insights and their implications for future study of human health and disease. ChIP-Seq for transcription factors in mouse embryonic stem cells and H3K27ac in Jurkat T-ALL cell line RNA-Seq for mouse embryonic stem cells

2013-10-23 | E-GEOD-51522 | biostudies-arrayexpress

Models of Human Core Transcriptional Regulatory Circuitries

Project description:A small set of core transcription factors (TFs) dominates control of the gene expression program in embryonic stem cells and other well-studied cellular models. These core TFs collectively regulate their own gene expression, thus forming an interconnected autoregulatory loop that can be considered the core transcriptional regulatory circuitry (CRC) for that cell type. There is limited knowledge of core TFs, and thus models of core regulatory circuitry, for most cell types. We recently discovered that genes encoding known core TFs forming CRCs are driven by super-enhancers, which provides an opportunity to systematically predict CRCs in poorly studied cell types through super-enhancer mapping. Here we use super-enhancer maps to generate CRC models for 75 human cell and tissue types. These core circuitry models should prove valuable for further investigating cell type-specific transcriptional regulation in healthy and diseased cells. ChIP-Seq for RUNX1 and GATA3 in Jurkat T cell acute lymphoblastic leukemia cells.

2015-12-18 | E-GEOD-76181 | biostudies-arrayexpress

Transcriptional super-enhancers connected to cell identity and disease

2013-10-23 | GSE51522 | GEO

Occupancy profiling of HAND2, MEIS2 and TCF4 by CUT&Tag from Neuroblastoma cells

Project description:HAND2, MEIS2 and TCF4 are master transcription factors (TFs) in neuroblastoma and create an interconnected core regulatory circuitry (CRC) by directly occupying each other's and their own super-enhancers (SEs), which leads to high levels of each TF expression inside the CRC. Additionally, CRC TFs cooperatively co-occupy the same SE components, which promotes the expression of genes involved in cell identity and cell-type-specific activities. Super-enhancer-mediated CRC enriched at key oncogenes in neuroblastoma. In the present study, CUT&Tag (Cleavage Under Targets and Tagmentation) analysis was performed to explore the target of HAND2, MEIS2 and TCF4 in NB cells.

2024-05-06 | GSE234337 | GEO

Cis-Regulatory Circuits Regulating NEK6 Kinase Overexpression in Transformed B Cells Are Super-Enhancer-Independent (RNA-seq)

Project description:Alterations in distal regulatory elements that control gene expression underlie many diseases, including cancer. Epigenomic analyses of normal and diseased cells have produced correlative predictions for connections between dysregulated enhancers and target genes involved in pathogenesis. However, with few exceptions, these predicted cis-regulatory circuits remain untested. Here, we dissect cis-regulatory circuits that lead to overexpression of NEK6, a mitosis-associated kinase, in human B cell lymphoma. We find that only a minor subset of predicted enhancers is required for NEK6 expression. Indeed, an annotated super-enhancer is dispensable for NEK6 overexpression and for maintaining the architecture of a B cell-specific regulatory hub. A CTCF cluster serves as a chromatin and architectural boundary to block communication of the NEK6 regulatory hub with neighboring genes. Our findings emphasize that validation of predicted cis-regulatory circuits and super-enhancers is needed to prioritize transcriptional control elements as therapeutic targets.

2017-02-23 | GSE87320 | GEO

Cis-Regulatory Circuits Regulating NEK6 Kinase Overexpression in Transformed B Cells Are Super-Enhancer-Independent (4C-seq)

2017-02-23 | GSE87322 | GEO

Epigenomic comparison of distinct pluripotent stem cell states reveals a new class of enhancers with roles throughout mammalian development (DNase-seq)

Project description:NaM-CM-/ve mouse embryonic stem cells (mESCs) and primed epiblast stem cells (mEpiSCs) represent successive snapshots of pluripotency during embryogenesis. Using transcriptomic and epigenomic mapping, we show that a small fraction of transcripts are differentially expressed between mESCs and mEpiSCs and these genes show expected changes in chromatin at their promoters and enhancers. Unexpectedly, the cis-regulatory circuitry of genes that are expressed at identical levels between these cell states also differs dramatically. In mESCs, these genes are associated with dominant proximal enhancers and dormant distal enhancers, which we term seed enhancers. In mEpiSCs, the naM-CM-/ve-dominant enhancers are lost, and the seed enhancers take up primary transcriptional control. Seed enhancers have increased sequence conservation and show preferential usage in downstream somatic tissues, often expanding into super enhancers. We propose that seed enhancers ensure proper enhancer utilization and transcriptional fidelity as mammalian cells transition from naM-CM-/ve pluripotency to a somatic regulatory program. DNase sequencing of histone modifications in mouse epiblast stem cells

2014-06-04 | E-GEOD-57406 | biostudies-arrayexpress

Epigenomic comparison of distinct pluripotent stem cell states reveals a new class of enhancers with roles throughout mammalian development (ChIP-seq)

Project description:NaM-CM-/ve mouse embryonic stem cells (mESCs) and primed epiblast stem cells (mEpiSCs) represent successive snapshots of pluripotency during embryogenesis. Using transcriptomic and epigenomic mapping, we show that a small fraction of transcripts are differentially expressed between mESCs and mEpiSCs and these genes show expected changes in chromatin at their promoters and enhancers. Unexpectedly, the cis-regulatory circuitry of genes that are expressed at identical levels between these cell states also differs dramatically. In mESCs, these genes are associated with dominant proximal enhancers and dormant distal enhancers, which we term seed enhancers. In mEpiSCs, the naM-CM-/ve-dominant enhancers are lost, and the seed enhancers take up primary transcriptional control. Seed enhancers have increased sequence conservation and show preferential usage in downstream somatic tissues, often expanding into super enhancers. We propose that seed enhancers ensure proper enhancer utilization and transcriptional fidelity as mammalian cells transition from naM-CM-/ve pluripotency to a somatic regulatory program. ChIP sequencing of histone modifications in mouse epiblast stem cells

2014-06-04 | E-GEOD-57407 | biostudies-arrayexpress

Epigenomic comparison of distinct pluripotent stem cell states reveals a new class of enhancers with roles throughout mammalian development (RNA-seq)

Project description:NaM-CM-/ve mouse embryonic stem cells (mESCs) and primed epiblast stem cells (mEpiSCs) represent successive snapshots of pluripotency during embryogenesis. Using transcriptomic and epigenomic mapping, we show that a small fraction of transcripts are differentially expressed between mESCs and mEpiSCs and these genes show expected changes in chromatin at their promoters and enhancers. Unexpectedly, the cis-regulatory circuitry of genes that are expressed at identical levels between these cell states also differs dramatically. In mESCs, these genes are associated with dominant proximal enhancers and dormant distal enhancers, which we term seed enhancers. In mEpiSCs, the naM-CM-/ve-dominant enhancers are lost, and the seed enhancers take up primary transcriptional control. Seed enhancers have increased sequence conservation and show preferential usage in downstream somatic tissues, often expanding into super enhancers. We propose that seed enhancers ensure proper enhancer utilization and transcriptional fidelity as mammalian cells transition from naM-CM-/ve pluripotency to a somatic regulatory program. RNA sequencing in quadruplicate of mouse embryonic stem cells and epiblast stem cells

2014-06-04 | E-GEOD-57403 | biostudies-arrayexpress

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