2. Academic Validation
  3. Mapping the Effects of Genetic Variation on Chromatin State and Gene Expression Reveals Loci That Control Ground State Pluripotency

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. doi: 10.1016/j.stem.2020.07.005.
Daniel A Skelly 1,  Anne Czechanski 1,  Candice Byers 2,  Selcan Aydin 1,  Catrina Spruce 1,  Chris Olivier 1,  Kwangbom Choi 1,  Daniel M Gatti 1,  Narayanan Raghupathy 1,  Gregory R Keele 1,  Alexander Stanton 2,  Matthew Vincent 1,  Stephanie Dion 1,  Ian Greenstein 1,  Matthew Pankratz 3,  Devin K Porter 3,  Whitney Martin 1,  Callan O'Connor 2,  Wenning Qin 1,  Alison H Harrill 4,  Ted Choi 3,  Gary A Churchill 5,  Steven C Munger 6,  Christopher L Baker 7,  Laura G Reinholdt 8
Affiliations

Affiliations

  • 1 The Jackson Laboratory, Bar Harbor, ME 04609, USA.
  • 2 The Jackson Laboratory, Bar Harbor, ME 04609, USA; Graduate School of Biomedical Sciences, Tufts University, Boston, MA 02111, USA.
  • 3 Predictive Biology, Carlsbad, CA 92010, USA.
  • 4 Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
  • 5 The Jackson Laboratory, Bar Harbor, ME 04609, USA; Graduate School of Biomedical Sciences, Tufts University, Boston, MA 02111, USA. Electronic address: gary.churchill@jax.org.
  • 6 The Jackson Laboratory, Bar Harbor, ME 04609, USA; Graduate School of Biomedical Sciences, Tufts University, Boston, MA 02111, USA. Electronic address: steven.munger@jax.org.
  • 7 The Jackson Laboratory, Bar Harbor, ME 04609, USA; Graduate School of Biomedical Sciences, Tufts University, Boston, MA 02111, USA. Electronic address: christopher.baker@jax.org.
  • 8 The Jackson Laboratory, Bar Harbor, ME 04609, USA. Electronic address: laura.reinholdt@jax.org.
PMID: 32795400 DOI: 10.1016/j.stem.2020.07.005
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.

Keywords

Diversity Outbred; Lifr; chromatin accessibility; gene expression; genetic variation; ground state pluripotency; mESC; metastability; quantitative trait locus.

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