Deterministic Somatic Cell Reprogramming Involves Continuous Transcriptional Changes Governed by Myc and Epigenetic-Driven Modules.
Animals
Cell Lineage
/ genetics
Cellular Reprogramming
/ genetics
Chromatin
/ metabolism
Demethylation
Epigenesis, Genetic
Humans
Induced Pluripotent Stem Cells
/ metabolism
Kruppel-Like Factor 4
Mice
Protein Binding
Proto-Oncogene Proteins c-myc
/ metabolism
RNA, Transfer
/ metabolism
Transcription Factors
/ metabolism
Transcription, Genetic
Gatad2a
Mbd3
Myc
NuRD
deterministic reprogramming
epigenetics
epigenomics
iPSC
pluripotency
Journal
Cell stem cell
ISSN: 1875-9777
Titre abrégé: Cell Stem Cell
Pays: United States
ID NLM: 101311472
Informations de publication
Date de publication:
07 02 2019
07 02 2019
Historique:
received:
21
02
2018
revised:
21
09
2018
accepted:
09
11
2018
pubmed:
18
12
2018
medline:
28
3
2020
entrez:
18
12
2018
Statut:
ppublish
Résumé
The epigenetic dynamics of induced pluripotent stem cell (iPSC) reprogramming in correctly reprogrammed cells at high resolution and throughout the entire process remain largely undefined. Here, we characterize conversion of mouse fibroblasts into iPSCs using Gatad2a-Mbd3/NuRD-depleted and highly efficient reprogramming systems. Unbiased high-resolution profiling of dynamic changes in levels of gene expression, chromatin engagement, DNA accessibility, and DNA methylation were obtained. We identified two distinct and synergistic transcriptional modules that dominate successful reprogramming, which are associated with cell identity and biosynthetic genes. The pluripotency module is governed by dynamic alterations in epigenetic modifications to promoters and binding by Oct4, Sox2, and Klf4, but not Myc. Early DNA demethylation at certain enhancers prospectively marks cells fated to reprogram. Myc activity drives expression of the essential biosynthetic module and is associated with optimized changes in tRNA codon usage. Our functional validations highlight interweaved epigenetic- and Myc-governed essential reconfigurations that rapidly commission and propel deterministic reprogramming toward naive pluripotency.
Identifiants
pubmed: 30554962
pii: S1934-5909(18)30550-2
doi: 10.1016/j.stem.2018.11.014
pmc: PMC7116520
mid: EMS108840
pii:
doi:
Substances chimiques
Chromatin
0
KLF4 protein, human
0
Klf4 protein, mouse
0
Kruppel-Like Factor 4
0
Proto-Oncogene Proteins c-myc
0
Transcription Factors
0
RNA, Transfer
9014-25-9
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
328-341.e9Subventions
Organisme : European Research Council
ID : 726497
Pays : International
Informations de copyright
Copyright © 2018 Elsevier Inc. All rights reserved.
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