title: cis-Acting Complex-Trait-Associated lincRNA Expression Correlates with Modulation of Chromosomal Architecture.
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.
authors.affiliation: 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.
authors.forename: Jennifer Yihong
authors.initials: JY
authors.lastname: Tan
authors.affiliation: Department of Physiology, University of Lausanne, 1015 Lausanne, Switzerland; Department of Computational Biology, University of Lausanne, 1015 Lausanne, Switzerland.
authors.forename: Adam Alexander Thil
authors.initials: AAT
authors.lastname: Smith
authors.affiliation: Department of Physiology, University of Lausanne, 1015 Lausanne, Switzerland; Department of Computational Biology, University of Lausanne, 1015 Lausanne, Switzerland.
authors.forename: Maria
authors.initials: M
authors.lastname: Ferreira da Silva
authors.affiliation: Department of Physiology, University of Lausanne, 1015 Lausanne, Switzerland; Department of Computational Biology, University of Lausanne, 1015 Lausanne, Switzerland.
authors.forename: Cyril
authors.initials: C
authors.lastname: Matthey-Doret
authors.affiliation: Department of Computational Biology, University of Lausanne, 1015 Lausanne, Switzerland; Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland.
authors.forename: Rico
authors.initials: R
authors.lastname: Rueedi
authors.affiliation: Department of Computational Biology, University of Lausanne, 1015 Lausanne, Switzerland; Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland.
authors.forename: Reyhan
authors.initials: R
authors.lastname: Sönmez
authors.affiliation: Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: David
authors.initials: D
authors.lastname: Ding
authors.affiliation: Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland; Institute of Social and Preventive Medicine, University Hospital Lausanne (CHUV), 1011 Lausanne, Switzerland.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Kutalik
authors.affiliation: Department of Computational Biology, University of Lausanne, 1015 Lausanne, Switzerland; Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland.
authors.forename: Sven
authors.initials: S
authors.lastname: Bergmann
authors.affiliation: 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.
authors.forename: Ana Claudia
authors.initials: AC
authors.lastname: Marques
mesh_terms: D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D002843:Chromatin / Q000235:genetics; D002875:Chromosomes / Q000235:genetics*; D015870:Gene Expression / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D020014:K562 Cells; D051379:Mice; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D040641:Quantitative Trait Loci / Q000235:genetics*; D062085:RNA, Long Noncoding / Q000235:genetics*
chemical_list: D002843:Chromatin; D062085:RNA, Long Noncoding
keywords: GWAS; TAD; cis-regulation; complex trait and disease; eQTL; enhancer; expression quantitative trait loci; intergenic long noncoding RNA; lincRNA; topologically associated domains