Subtle changes in chromatin loop contact propensity are associated with differential gene regulation and expression.

TitleSubtle changes in chromatin loop contact propensity are associated with differential gene regulation and expression.
Publication TypeJournal Article
Year of Publication2019
AuthorsGreenwald, WW, Li, H, Benaglio, P, Jakubosky, D, Matsui, H, Schmitt, A, Selvaraj, S, D'Antonio, M, D'Antonio-Chronowska, A, Smith, EN, Frazer, KA
JournalNat Commun
Volume10
Issue1
Pagination1054
Date Published2019 03 05
ISSN2041-1723
KeywordsAdolescent, Adult, Aged, Cell Line, Chromatin, DNA, Female, Gene Expression Regulation, Histones, Humans, Induced Pluripotent Stem Cells, Male, Middle Aged, Myocytes, Cardiac, Nucleic Acid Conformation, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Whole Genome Sequencing, Young Adult
Abstract

While genetic variation at chromatin loops is relevant for human disease, the relationships between contact propensity (the probability that loci at loops physically interact), genetics, and gene regulation are unclear. We quantitatively interrogate these relationships by comparing Hi-C and molecular phenotype data across cell types and haplotypes. While chromatin loops consistently form across different cell types, they have subtle quantitative differences in contact frequency that are associated with larger changes in gene expression and H3K27ac. For the vast majority of loci with quantitative differences in contact frequency across haplotypes, the changes in magnitude are smaller than those across cell types; however, the proportional relationships between contact propensity, gene expression, and H3K27ac are consistent. These findings suggest that subtle changes in contact propensity have a biologically meaningful role in gene regulation and could be a mechanism by which regulatory genetic variants in loop anchors mediate effects on expression.

DOI10.1038/s41467-019-08940-5
Alternate JournalNat Commun
PubMed ID30837461
PubMed Central IDPMC6401380
Grant ListU01 DK105541 / DK / NIDDK NIH HHS / United States
DP3 DK112155 / DK / NIDDK NIH HHS / United States
R41 HG008118 / HG / NHGRI NIH HHS / United States
U01 HL107442 / HL / NHLBI NIH HHS / United States
T15 LM011271 / LM / NLM NIH HHS / United States
F31 HL142151 / HL / NHLBI NIH HHS / United States
P30 CA023100 / CA / NCI NIH HHS / United States
R44 HG008118 / HG / NHGRI NIH HHS / United States