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
Affiliations
Jennifer Yihong Tan
Department of Physiology, University of Lausanne, 1015 Lausanne, Switzerland; Department of Computational Biology, University of Lausanne, 1015 Lausanne, Switzerland; Corresponding author
Adam Alexander Thil Smith
Department of Physiology, University of Lausanne, 1015 Lausanne, Switzerland; Department of Computational Biology, University of Lausanne, 1015 Lausanne, Switzerland
Maria Ferreira da Silva
Department of Physiology, University of Lausanne, 1015 Lausanne, Switzerland; Department of Computational Biology, University of Lausanne, 1015 Lausanne, Switzerland
Cyril Matthey-Doret
Department of Physiology, University of Lausanne, 1015 Lausanne, Switzerland; Department of Computational Biology, University of Lausanne, 1015 Lausanne, Switzerland
Rico Rueedi
Department of Computational Biology, University of Lausanne, 1015 Lausanne, Switzerland; Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland
Reyhan Sönmez
Department of Computational Biology, University of Lausanne, 1015 Lausanne, Switzerland; Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland
David Ding
Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA
Zoltán Kutalik
Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland; Institute of Social and Preventive Medicine, University Hospital Lausanne (CHUV), 1011 Lausanne, Switzerland
Sven Bergmann
Department of Computational Biology, University of Lausanne, 1015 Lausanne, Switzerland; Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland
Ana Claudia Marques
Department of Physiology, University of Lausanne, 1015 Lausanne, Switzerland; Department of Computational Biology, University of Lausanne, 1015 Lausanne, Switzerland; Corresponding author
Summary: 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. : Tan et al. identify and characterize 69 human complex trait/disease-associated lincRNAs in LCLs. They show that these loci are often associated with cis-regulation of gene expression and tend to be localized at TAD boundaries, suggesting that these lincRNAs may influence chromosomal architecture. Keywords: intergenic long noncoding RNA, lincRNA, GWAS, expression quantitative trait loci, eQTL, complex trait and disease, enhancer, cis-regulation, topologically associated domains, TAD
