Mapping the Effects of Genetic Variation on Chromatin State and Gene Expression Reveals Loci That Control Ground State Pluripotency.
Document Type
Article
Publication Date
9-3-2020
Keywords
JMG, JAXCC
JAX Source
Cell Stem Cell 2020 Sep 3; 27(3):459-469.e8
Volume
27
Issue
3
First Page
459
Last Page
469
ISSN
1875-9777
PMID
32795400
DOI
https://doi.org/10.1016/j.stem.2020.07.005
Grant
OD010921, OD011102, GM133724, GM070683, T32HD007065, DA039841, GM133495, CA034196
Abstract
Mouse embryonic stem cells (mESCs) cultured in the presence of LIF occupy a ground state with highly active pluripotency-associated transcriptional and epigenetic circuitry. However, ground state pluripotency in some inbred strain backgrounds is unstable in the absence of ERK1/2 and GSK3 inhibition. Using an unbiased genetic approach, we dissect the basis of this divergent response to extracellular cues by profiling gene expression and chromatin accessibility in 170 genetically heterogeneous mESCs. We map thousands of loci affecting chromatin accessibility and/or transcript abundance, including 10 QTL hotspots where genetic variation at a single locus coordinates the regulation of genes throughout the genome. For one hotspot, we identify a single enhancer variant ∼10 kb upstream of Lifr associated with chromatin accessibility and mediating a cascade of molecular events affecting pluripotency. We validate causation through reciprocal allele swaps, demonstrating the functional consequences of noncoding variation in gene regulatory networks that stabilize pluripotent states in vitro.
Recommended Citation
Skelly D,
Czechanski A,
Byers C,
Aydin S,
Spruce C,
Olivier C,
Choi K,
Gatti D,
Raghupathy N,
Keele G,
Stanton A,
Vincent M,
Dion SL,
Greenstein I,
Pankratz M,
Porter D,
Martin W,
O'Connor C,
Qin W,
Harrill A,
Choi T,
Churchill G,
Munger SC,
Baker CL,
Reinholdt L.
Mapping the Effects of Genetic Variation on Chromatin State and Gene Expression Reveals Loci That Control Ground State Pluripotency. Cell Stem Cell 2020 Sep 3; 27(3):459-469.e8
Comments
We thank David Aylor and Thomas Konneker for early contributions in the analysis of the inbred strain transcriptome data; Steve Murray, Kevin Peterson, and Susan Kales for sharing plasmids; and Martin Pera and Daniel Cortes-Perez for constructive feedback on the project and manuscript. Additionally, we recognize Richard Paules and Kristine Witt for contributing to the development of the DO mESCs, Alex Merrick of the National Institute of Environmental Health Sciences (NIEHS) for reviewing the manuscript, and Charles Farber and Emily Farber of The University of Virginia Genome Analysis and Technology Core for providing sequencing services and support and the Jackson Laboratory Genome Technologies Service.