Human cardiac cis-regulatory elements, their cognate transcription factors, and regulatory DNA sequence variants
- Dongwon Lee1,4,
- Ashish Kapoor1,5,
- Alexias Safi2,
- Lingyun Song2,
- Marc K. Halushka3,
- Gregory E. Crawford2 and
- Aravinda Chakravarti1,4
- 1McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA;
- 2Department of Pediatrics and Center for Genomic and Computational Biology, Duke University Medical Center, Durham, North Carolina 27708, USA;
- 3Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
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.
Footnotes
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.234633.118.
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Freely available online through the Genome Research Open Access option.
- Received January 11, 2018.
- Accepted August 16, 2018.
This article, published in Genome Research, is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
