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Genetic variation influences pluripotent ground state stability in mouse embryonic stem cells through a hierarchy of molecular phenotypes

View ORCID ProfileDaniel A. Skelly, View ORCID ProfileAnne Czechanski, View ORCID ProfileCandice Byers, View ORCID ProfileSelcan Aydin, Catrina Spruce, Chris Olivier, View ORCID ProfileKwangbom Choi, Daniel M. Gatti, View ORCID ProfileNarayanan Raghupathy, View ORCID ProfileAlexander Stanton, Matthew Vincent, Stephanie Dion, Ian Greenstein, View ORCID ProfileMatthew Pankratz, Devin K. Porter, Whitney Martin, View ORCID ProfileWenning Qin, Alison H. Harrill, Ted Choi, View ORCID ProfileGary A. Churchill, View ORCID ProfileSteven C. Munger, View ORCID ProfileChristopher L. Baker, View ORCID ProfileLaura G. Reinholdt
doi: https://doi.org/10.1101/552059
Daniel A. Skelly
1The Jackson Laboratory, Bar Harbor, Maine 04609
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Anne Czechanski
1The Jackson Laboratory, Bar Harbor, Maine 04609
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Candice Byers
1The Jackson Laboratory, Bar Harbor, Maine 04609
2Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, MA 02111
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Selcan Aydin
1The Jackson Laboratory, Bar Harbor, Maine 04609
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Catrina Spruce
1The Jackson Laboratory, Bar Harbor, Maine 04609
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Chris Olivier
1The Jackson Laboratory, Bar Harbor, Maine 04609
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Kwangbom Choi
1The Jackson Laboratory, Bar Harbor, Maine 04609
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Daniel M. Gatti
1The Jackson Laboratory, Bar Harbor, Maine 04609
3Predictive Biology, Inc., Carlsbad, CA 92010
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Narayanan Raghupathy
1The Jackson Laboratory, Bar Harbor, Maine 04609
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Alexander Stanton
1The Jackson Laboratory, Bar Harbor, Maine 04609
2Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, MA 02111
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Matthew Vincent
1The Jackson Laboratory, Bar Harbor, Maine 04609
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Stephanie Dion
1The Jackson Laboratory, Bar Harbor, Maine 04609
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Ian Greenstein
1The Jackson Laboratory, Bar Harbor, Maine 04609
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Matthew Pankratz
3Predictive Biology, Inc., Carlsbad, CA 92010
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Devin K. Porter
3Predictive Biology, Inc., Carlsbad, CA 92010
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Whitney Martin
1The Jackson Laboratory, Bar Harbor, Maine 04609
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Wenning Qin
1The Jackson Laboratory, Bar Harbor, Maine 04609
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Alison H. Harrill
4Division of the National Toxicology Program, the National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709
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Ted Choi
3Predictive Biology, Inc., Carlsbad, CA 92010
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Gary A. Churchill
1The Jackson Laboratory, Bar Harbor, Maine 04609
2Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, MA 02111
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  • For correspondence: laura.reinholdt@jax.org christopher.baker@jax.org steven.munger@jax.org gary.churchill@jax.org
Steven C. Munger
1The Jackson Laboratory, Bar Harbor, Maine 04609
2Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, MA 02111
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  • For correspondence: laura.reinholdt@jax.org christopher.baker@jax.org steven.munger@jax.org gary.churchill@jax.org
Christopher L. Baker
1The Jackson Laboratory, Bar Harbor, Maine 04609
2Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, MA 02111
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  • For correspondence: laura.reinholdt@jax.org christopher.baker@jax.org steven.munger@jax.org gary.churchill@jax.org
Laura G. Reinholdt
1The Jackson Laboratory, Bar Harbor, Maine 04609
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  • For correspondence: laura.reinholdt@jax.org christopher.baker@jax.org steven.munger@jax.org gary.churchill@jax.org
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Abstract

Mouse embryonic stem cells (mESCs) cultured under controlled conditions occupy a stable ground state where pluripotency-associated transcriptional and epigenetic circuitry are highly active. However, mESCs from some genetic backgrounds exhibit metastability, where ground state pluripotency is lost in the absence of ERK1/2 and GSK3 inhibition. We dissected the genetic basis of metastability by profiling gene expression and chromatin accessibility in 185 genetically heterogeneous mESCs. We mapped thousands of loci affecting chromatin accessibility and/or transcript abundance, including eleven instances where distant QTL co-localized in clusters. For one cluster we identified Lifr transcript abundance as the causal intermediate regulating 122 distant genes enriched for roles in maintenance of pluripotency. Joint mediation analysis implicated a single enhancer variant ~10kb upstream of Lifr that alters chromatin accessibility and precipitates a cascade of molecular events affecting maintenance of pluripotency. We validated this hypothesis using reciprocal allele swaps, revealing mechanistic details underlying variability in ground state metastability in mESCs.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted February 17, 2019.
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Genetic variation influences pluripotent ground state stability in mouse embryonic stem cells through a hierarchy of molecular phenotypes
Daniel A. Skelly, Anne Czechanski, Candice Byers, Selcan Aydin, Catrina Spruce, Chris Olivier, Kwangbom Choi, Daniel M. Gatti, Narayanan Raghupathy, Alexander Stanton, Matthew Vincent, Stephanie Dion, Ian Greenstein, Matthew Pankratz, Devin K. Porter, Whitney Martin, Wenning Qin, Alison H. Harrill, Ted Choi, Gary A. Churchill, Steven C. Munger, Christopher L. Baker, Laura G. Reinholdt
bioRxiv 552059; doi: https://doi.org/10.1101/552059
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Genetic variation influences pluripotent ground state stability in mouse embryonic stem cells through a hierarchy of molecular phenotypes
Daniel A. Skelly, Anne Czechanski, Candice Byers, Selcan Aydin, Catrina Spruce, Chris Olivier, Kwangbom Choi, Daniel M. Gatti, Narayanan Raghupathy, Alexander Stanton, Matthew Vincent, Stephanie Dion, Ian Greenstein, Matthew Pankratz, Devin K. Porter, Whitney Martin, Wenning Qin, Alison H. Harrill, Ted Choi, Gary A. Churchill, Steven C. Munger, Christopher L. Baker, Laura G. Reinholdt
bioRxiv 552059; doi: https://doi.org/10.1101/552059

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