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

Dongwon Lee, Ashish Kapoor, Alexias Safi, Lingyun Song, Marc K. Halushka, Gregory E. Crawford, Aravinda Chakravarti

Research output: Contribution to journalArticlepeer-review

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 sequencebased 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.

Original languageEnglish (US)
Pages (from-to)1577-1588
Number of pages12
JournalGenome research
Volume28
Issue number10
DOIs
StatePublished - Oct 2018

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Fingerprint

Dive into the research topics of 'Human cardiac cis-regulatory elements, their cognate transcription factors, and regulatory DNA sequence variants'. Together they form a unique fingerprint.

Cite this