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A cis-regulatory lexicon of DNA motif combinations mediating cell type-specific gene regulation [ATAC-Seq]

ABSTRACT: Abstract: Gene expression is controlled by transcription factors (TFs) that bind cognate DNA motifs in cis-regulatory elements (CREs), however, the combinations of motifs that mediate cell type-specific gene regulation are undefined. Chromatin accessibility, TF footprinting, and H3K27ac-dependent DNA looping data were generated to identify 7,531 cell type-specific CREs across 15 normal human cell types. A co-enrichment framework nominated 838 cell type-specific, recurrent heterotypic DNA motif combinations (DMCs), which were functionally validated using massively parallel reporter assays. Compared to their normal counterparts, cancer cells induced DMCs linked to neoplasia-enabling processes that operate in normal cells while also engaging entirely new DMCs. These data identify a cis-regulatory combinatorial DNA motif lexicon for cell type-specific gene regulation in diverse normal and diseased human cells. Purpose: To identify a cis-regulatory combinatorial DNA motif lexicon mediating cell type-specific gene regulation in diverse normal and diseased human cells, matched RNA-seq, chromatin accessibility profiling via ATAC-seq, and enhancer-promoter looping via H3K27ac HiChIP was performed in 15 primary human cell types and 6 human cancer cell lines. Processed and raw data for all cell types can be found in this repository. Squamous cell carcinoma cell line raw and processed data can be found at Jung, et al. "XXX". All biological replicates (n=2) are merged.

ORGANISM(S): Homo sapiens

PROVIDER: GSE188398 | GEO | 2022/08/17

REPOSITORIES: GEO

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A cis-regulatory lexicon of DNA motif combinations mediating cell type-specific gene regulation [HiChIP-Seq]

Project description:Abstract: Gene expression is controlled by transcription factors (TFs) that bind cognate DNA motifs in cis-regulatory elements (CREs), however, the combinations of motifs that mediate cell type-specific gene regulation are undefined. Chromatin accessibility, TF footprinting, and H3K27ac-dependent DNA looping data were generated to identify 7,531 cell type-specific CREs across 15 normal human cell types. A co-enrichment framework nominated 838 cell type-specific, recurrent heterotypic DNA motif combinations (DMCs), which were functionally validated using massively parallel reporter assays. Compared to their normal counterparts, cancer cells induced DMCs linked to neoplasia-enabling processes that operate in normal cells while also engaging entirely new DMCs. These data identify a cis-regulatory combinatorial DNA motif lexicon for cell type-specific gene regulation in diverse normal and diseased human cells. Purpose: To identify a cis-regulatory combinatorial DNA motif lexicon mediating cell type-specific gene regulation in diverse normal and diseased human cells, matched RNA-seq, chromatin accessibility profiling via ATAC-seq, and enhancer-promoter looping via H3K27ac HiChIP was performed in 15 primary human cell types and 6 human cancer cell lines. Processed and raw data for all cell types can be found in this repository. Squamous cell carcinoma cell line raw and processed data can be found at Jung, et al. "XXX". All biological replicates (n=2) are merged.

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A cis-regulatory atlas of maize single cells

Project description:Cis-regulatory elements (CREs) encode the genomic blueprints for coordinating the spatiotemporal regulation of gene transcription programs necessary for highly specialized cellular functions. To identify cis-regulatory elements underlying cell-type specification and developmental transitions, we implemented single-cell sequencing of Assay for Transposase Accessible Chromatin (scATAC-seq) in an atlas of Zea mays tissues and organs. We describe 92 distinct patterns of chromatin accessibility across more than 165,913 putative CREs, greater than 56,575 cells, and 52 known cell-types using a novel regularized quasibinomial logistic model for estimating single cell accessibility. Cell-type specification could be largely explained by combinatorial accessibility of transcription factors (TFs) and their associated binding. Analysis of cell type-specific co-accessible chromatin recapitulated higher-order chromatin interactions, providing novel insight into cell type-specific regulatory dynamics. Integration of genetic diversity data revealed cell-type specific CREs contributed to specific morphological and molecular phenotypic traits indicative of their cellular functions, expanding our understanding of the molecular influence of complex traits in a eukaryotic species.

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Project description:A fundamental challenge in genomics is to map DNA sequence variants onto changes in gene expression. Gene expression is regulated by cis-regulatory elements (CREs, i.e., enhancers, promoters, and silencers) and the trans factors (e.g., transcription factors) that act upon them. A powerful approach to dissecting cis and trans effects is to compare F1 hybrids with F0 homozygotes. Using this approach and taking advantage of the high frequency of polymorphisms in wild-derived inbred Cast/EiJ mice relative to the reference strain C57BL/6J, we conducted allele-specific mRNA-seq analysis in the adult mouse retina, a disease-relevant neural tissue. We found that cis effects account for the bulk of gene regulatory divergence in the retina. Many CREs contained functional (i.e., activating or silencing) cis-regulatory variants mapping onto altered expression of genes, including genes associated with retinal disease. By comparing our retinal data with previously published liver data, we found that most of the cis effects identified were tissue-specific. Lastly, by comparing reciprocal F1 hybrids, we identified evidence of imprinting in the retina for the first time. Our study provides a framework and resource for mapping cis-regulatory variants onto changes in gene expression, and underscores the importance of studying cis-regulatory variants in the context of retinal disease. Retinas from four classes of 8 week old male mice were collected: F0 C57BL/6J (B6), F0 Cast/EiJ (Cast), F1 B6xCast, and F1 CastxB6. Three replicates per class were generated. Each replicate consisted of a pool of 6-8 retinas. The mRNA-seq was conducted with paired-end 2x101 sequencing on the Illumina HiSeq 2000 platform. One lane of sequencing was run for all twelve samples. An additional lane of sequencing was run for the six F1 samples.

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