Dataset Information

Human cardiac cis-regulatory elements, their cognate transcription factors, and regulatory DNA sequence variants.

ABSTRACT: Cis-regulatory elements (CRE), short DNA sequences through which transcription factors (TFs) exert regulatory control on gene expression, are postulated to be the major sites of causal sequence variation underlying the genetics of complex traits and diseases. We present integrative analyses, combining high-throughput genomic and epigenomic data with sequence-based computations, to identify the causal transcriptional components in a given tissue. We use data on adult human hearts to demonstrate that (1) sequence-based predictions detect numerous, active, tissue-specific CREs missed by experimental observations, (2) learned sequence features identify the cognate TFs, (3) CRE variants are specifically associated with cardiac gene expression, and (4) a significant fraction of the heritability of exemplar cardiac traits (QT interval, blood pressure, pulse rate) is attributable to these variants. This general systems approach can thus identify candidate causal variants and the components of gene regulatory networks (GRN) to enable understanding of the mechanisms of complex disorders on a tissue- or cell-type basis.

SUBMITTER: Lee D

PROVIDER: S-EPMC6169896 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Human cardiac <i>cis</i>-regulatory elements, their cognate transcription factors, and regulatory DNA sequence variants.

Lee Dongwon D Kapoor Ashish A Safi Alexias A Song Lingyun L Halushka Marc K MK Crawford Gregory E GE Chakravarti Aravinda A

Genome research 20180823 10

<i>Cis</i>-regulatory elements (CRE), short DNA sequences through which transcription factors (TFs) exert regulatory control on gene expression, are postulated to be the major sites of causal sequence variation underlying the genetics of complex traits and diseases. We present integrative analyses, combining high-throughput genomic and epigenomic data with sequence-based computations, to identify the causal transcriptional components in a given tissue. We use data on adult human hearts to demons ...[more]

PMID: 30139769

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Project description:It is now established that, as compared to normal cells, the cancer cell genome has an overall inverse distribution of DNA methylation ("methylome"), i.e., predominant hypomethylation and localized hypermethylation, within "CpG islands" (CGIs). Moreover, although cancer cells have reduced methylation "fidelity" and genomic instability, accurate maintenance of aberrant methylomes that underlie malignant phenotypes remains necessary. However, the mechanism(s) of cancer methylome maintenance remains largely unknown. Here, we assessed CGI methylation patterns propagated over 1, 3, and 5 divisions of A2780 ovarian cancer cells, concurrent with exposure to the DNA cross-linking chemotherapeutic cisplatin, and observed cell generation-successive increases in total hyper- and hypo-methylated CGIs. Empirical bayesian modeling revealed five distinct modes of methylation propagation: (1) heritable (i.e., unchanged) high-methylation (1186 probe loci in CGI microarray); (2) heritable (i.e., unchanged) low-methylation (286 loci); (3) stochastic hypermethylation (i.e., progressively increased, 243 loci); (4) stochastic hypomethylation (i.e., progressively decreased, 247 loci); and (5) considerable "random" methylation (582 loci). These results support a "stochastic model" of DNA methylation equilibrium deriving from the efficiency of two distinct processes, methylation maintenance and de novo methylation. A role for cis-regulatory elements in methylation fidelity was also demonstrated by highly significant (p<2.2×10(-5)) enrichment of transcription factor binding sites in CGI probe loci showing heritably high (118 elements) and low (47 elements) methylation, and also in loci demonstrating stochastic hyper-(30 elements) and hypo-(31 elements) methylation. Notably, loci having "random" methylation heritability displayed nearly no enrichment. These results demonstrate an influence of cis-regulatory elements on the nonrandom propagation of both strictly heritable and stochastically heritable CGIs.

Dataset Information

Human cardiac cis-regulatory elements, their cognate transcription factors, and regulatory DNA sequence variants.

Publications

Human cardiac <i>cis</i>-regulatory elements, their cognate transcription factors, and regulatory DNA sequence variants.

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