Mapping the Effects of Genetic Variation on Chromatin State and Gene Expression Reveals Loci That Control Ground State Pluripotency.
Diversity Outbred
Lifr
chromatin accessibility
gene expression
genetic variation
ground state pluripotency
mESC
metastability
quantitative trait locus
Journal
Cell stem cell
ISSN: 1875-9777
Titre abrégé: Cell Stem Cell
Pays: United States
ID NLM: 101311472
Informations de publication
Date de publication:
03 09 2020
03 09 2020
Historique:
received:
26
02
2019
revised:
07
02
2020
accepted:
02
07
2020
pubmed:
17
8
2020
medline:
28
4
2021
entrez:
16
8
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32795400
pii: S1934-5909(20)30343-X
doi: 10.1016/j.stem.2020.07.005
pmc: PMC7484384
mid: NIHMS1620410
pii:
doi:
Substances chimiques
Chromatin
0
Glycogen Synthase Kinase 3
EC 2.7.11.26
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
459-469.e8Subventions
Organisme : NIDA NIH HHS
ID : P50 DA039841
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM133724
Pays : United States
Organisme : NICHD NIH HHS
ID : T32 HD007065
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA034196
Pays : United States
Organisme : NIH HHS
ID : P40 OD011102
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM133495
Pays : United States
Organisme : NIH HHS
ID : U42 OD010921
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM070683
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2020 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Interests T.C. and D.K.P. have an equity interest in Predictive Biology.
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