cis-Acting Complex-Trait-Associated lincRNA Expression Correlates with Modulation of Chromosomal Architecture

Jennifer Yihong Tan; Adam Alexander Thil Smith; Maria Ferreira da Silva; Cyril Matthey-Doret; Rico Rueedi; Reyhan Sönmez; David Ding; Zoltán Kutalik; Sven Bergmann; Ana Claudia Marques

doi:10.1016/j.celrep.2017.02.009

cis-Acting Complex-Trait-Associated lincRNA Expression Correlates with Modulation of Chromosomal Architecture

Cell Rep. 2017 Feb 28;18(9):2280-2288. doi: 10.1016/j.celrep.2017.02.009.

Affiliations

¹ Department of Physiology, University of Lausanne, 1015 Lausanne, Switzerland; Department of Computational Biology, University of Lausanne, 1015 Lausanne, Switzerland. Electronic address: jennifer.tan@unil.ch.
² Department of Physiology, University of Lausanne, 1015 Lausanne, Switzerland; Department of Computational Biology, University of Lausanne, 1015 Lausanne, Switzerland.
³ Department of Computational Biology, University of Lausanne, 1015 Lausanne, Switzerland; Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland.
⁴ Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
⁵ Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland; Institute of Social and Preventive Medicine, University Hospital Lausanne (CHUV), 1011 Lausanne, Switzerland.
⁶ Department of Physiology, University of Lausanne, 1015 Lausanne, Switzerland; Department of Computational Biology, University of Lausanne, 1015 Lausanne, Switzerland. Electronic address: anaclaudia.marques@unil.ch.

PMID: 28249171
DOI: 10.1016/j.celrep.2017.02.009

Abstract

Intergenic long noncoding RNAs (lincRNAs) are the largest class of transcripts in the human genome. Although many have recently been linked to complex human traits, the underlying mechanisms for most of these transcripts remain undetermined. We investigated the regulatory roles of a high-confidence and reproducible set of 69 trait-relevant lincRNAs (TR-lincRNAs) in human lymphoblastoid cells whose biological relevance is supported by their evolutionary conservation during recent human history and genetic interactions with other trait-associated loci. Their enrichment in enhancer-like chromatin signatures, interactions with nearby trait-relevant protein-coding loci, and preferential location at topologically associated domain (TAD) boundaries provide evidence that TR-lincRNAs likely regulate proximal trait-relevant gene expression in cis by modulating local chromosomal architecture. This is consistent with the positive and significant correlation found between TR-lincRNA abundance and intra-TAD DNA-DNA contacts. Our results provide insights into the molecular mode of action by which TR-lincRNAs contribute to complex human traits.

Keywords: GWAS; TAD; cis-regulation; complex trait and disease; eQTL; enhancer; expression quantitative trait loci; intergenic long noncoding RNA; lincRNA; topologically associated domains.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Line
Cell Line, Tumor
Chromatin / genetics
Chromosomes / genetics*
Gene Expression / genetics
Gene Expression Regulation / genetics*
Human Umbilical Vein Endothelial Cells
Humans
K562 Cells
Mice
Polymorphism, Single Nucleotide / genetics*
Quantitative Trait Loci / genetics*
RNA, Long Noncoding / genetics*

Substances

Chromatin
RNA, Long Noncoding