Document Type
Article
Publication Date
4-26-2024
Original Citation
Kuffler L,
Skelly D,
Czechanski A,
Fortin H,
Munger SC,
Baker CL,
Reinholdt L,
Carter GW.
Imputation of 3D genome structure by genetic-epigenetic interaction modeling in mice. Elife. 2024;12:RP88222.
Keywords
JMG, Animals, Mice, Epigenesis, Genetic, Chromatin, Genome, Genetic Variation, Embryonic Stem Cells
JAX Source
Elife. 2024;12:RP88222.
ISSN
2050-084X
PMID
38669177
DOI
https://doi.org/10.7554/eLife.88222
Grant
National Institute of General Medical Sciences R01GM115518 Gregory W Carter, National Institute of General Medical Sciences R35GM133724 Christopher L Baker, National Institutes of Health P40OD011102 Laura G Reinholdt
Abstract
Gene expression is known to be affected by interactions between local genetic variation and DNA accessibility, with the latter organized into three-dimensional chromatin structures. Analyses of these interactions have previously been limited, obscuring their regulatory context, and the extent to which they occur throughout the genome. Here, we undertake a genome-scale analysis of these interactions in a genetically diverse population to systematically identify global genetic-epigenetic interaction, and reveal constraints imposed by chromatin structure. We establish the extent and structure of genotype-by-epigenotype interaction using embryonic stem cells derived from Diversity Outbred mice. This mouse population segregates millions of variants from eight inbred founders, enabling precision genetic mapping with extensive genotypic and phenotypic diversity. With 176 samples profiled for genotype, gene expression, and open chromatin, we used regression modeling to infer genetic-epigenetic interactions on a genome-wide scale. Our results demonstrate that statistical interactions between genetic variants and chromatin accessibility are common throughout the genome. We found that these interactions occur within the local area of the affected gene, and that this locality corresponds to topologically associated domains (TADs). The likelihood of interaction was most strongly defined by the three-dimensional (3D) domain structure rather than linear DNA sequence. We show that stable 3D genome structure is an effective tool to guide searches for regulatory elements and, conversely, that regulatory elements in genetically diverse populations provide a means to infer 3D genome structure. We confirmed this finding with CTCF ChIP-seq that revealed strain-specific binding in the inbred founder mice. In stem cells, open chromatin participating in the most significant regression models demonstrated an enrichment for developmental genes and the TAD-forming CTCF-binding complex, providing an opportunity for statistical inference of shifting TAD boundaries operating during early development. These findings provide evidence that genetic and epigenetic factors operate within the context of 3D chromatin structure.
Comments
Copyright Kuffler et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.