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Nat Commun. 2019 Mar 5;10(1):1054. doi: 10.1038/s41467-019-08940-5.

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

Author information

1
Bioinformatics and Systems Biology Graduate Program, University of California, San Diego, La Jolla, CA, 92093, USA.
2
Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA, 92093, USA.
3
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030, USA.
4
Department of Pediatrics and Rady Children's Hospital, University of California, San Diego, La Jolla, CA, 92093, USA.
5
Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA, 92093, USA.
6
Department of Biomedical Sciences, University of California, San Diego, La Jolla, CA, 92093, USA.
7
Arima Genomics, San Diego, CA, 92121, USA.
8
Moores Cancer Center, University of California, San Diego, La Jolla, CA, 92093, USA.
9
Department of Pediatrics and Rady Children's Hospital, University of California, San Diego, La Jolla, CA, 92093, USA. erinnsmith@gmail.com.
10
Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA, 92093, USA. kafrazer@ucsd.edu.
11
Department of Pediatrics and Rady Children's Hospital, University of California, San Diego, La Jolla, CA, 92093, USA. kafrazer@ucsd.edu.

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.

PMID:
30837461
PMCID:
PMC6401380
DOI:
10.1038/s41467-019-08940-5
[Indexed for MEDLINE]
Free PMC Article

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