气候变化领域集成服务门户(CCPortal): AP-1 is a temporally regulated dual gatekeeper of reprogramming to pluripotency

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DOI	10.1073/PNAS.2104841118
	AP-1 is a temporally regulated dual gatekeeper of reprogramming to pluripotency
	Markov G.J.; Mai T.; Nair S.; Shcherbina A.; Wang Y.X.; Burns D.M.; Kundaje A.; Blau H.M.
发表日期	2021
ISSN	0027-8424
卷号	118 期号:23
英文摘要	Somatic cell transcription factors are critical to maintaining cellular identity and constitute a barrier to human somatic cell reprogramming; yet a comprehensive understanding of the mechanism of action is lacking. To gain insight, we examined epigenome remodeling at the onset of human nuclear reprogramming by profiling human fibroblasts after fusion with murine embryonic stem cells (ESCs). By assay for transposase-accessible chromatin with highthroughput sequencing (ATAC-seq) and chromatin immunoprecipitation sequencingwe identified enrichment for the activator protein 1 (AP-1) transcription factor c-Jun at regions of early transient accessibility at fibroblast-specific enhancers. Expression of a dominant negative AP-1 mutant (dnAP-1) reduced accessibility and expression of fibroblast genes, overcoming the barrier to reprogramming. Remarkably, efficient reprogramming of human fibroblasts to induced pluripotent stem cells was achieved by transduction with vectors expressing SOX2, KLF4, and inducible dnAP-1, demonstrating that dnAP-1 can substitute for exogenous human OCT4. Mechanistically, we show that the AP-1 component c-Jun has two unexpected temporally distinct functions in human reprogramming: 1) to potentiate fibroblast enhancer accessibility and fibroblast-specific gene expression, and 2) to bind to and repress OCT4 as a complex with MBD3. Our findings highlight AP-1 as a previously unrecognized potent dual gatekeeper of the somatic cell state. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	C-Jun; Heterokaryon; Reprogramming pluripotency; Transcription factor
语种	英语
scopus关键词	beta catenin; interleukin 2; kruppel like factor 4; mitogen activated protein kinase 1; mitogen activated protein kinase 3; octamer transcription factor 4; protein c jun; protein p53; small interfering RNA; transcription factor; transcription factor AP 1; transcription factor Sox2; transcriptome; transposase; Twist related protein 2; transcription factor AP 1; Article; cell differentiation; cell proliferation; chromatin immunoprecipitation; chromatin immunoprecipitation sequencing; controlled study; down regulation; embryonic stem cell; enhancer region; epigenome; epithelial mesenchymal transition; fibroblast; gene cluster; gene expression; gene mutation; gene ontology; gene overexpression; genetic transcription; heterokaryon; high throughput sequencing; histone modification; human; human cell; immunoblotting; immunoprecipitation; induced pluripotent stem cell; luciferase assay; mouse embryonic stem cell; MRC-5 cell line; nerve cell network; nuclear reprogramming; pluripotent stem cell; protein expression; protein fingerprinting; protein phosphorylation; protein protein interaction; RNA sequence; Schizosaccharomyces pombe; single nucleotide polymorphism; somatic cell; transcription initiation; transcription regulation; upregulation; animal; cell line; gene expression regulation; genetics; metabolism; mouse; Animals; Cell Line; Cellular Reprogramming; Gene Expression Regulation; Humans; Mice; Mouse Embryonic Stem Cells; Transcription Factor AP-1
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/251199
作者单位	Baxter Laboratory for Stem Cell Biology, Stanford University, School of Medicine, Stanford, CA 94305, United States; Department of Genetics, Stanford University, Stanford, CA 94305, United States; Department of Computer Science, Stanford University, Stanford, CA 94305, United States; Biomedical Informatics, Stanford University, Stanford, CA 94305, United States
推荐引用方式 GB/T 7714	Markov G.J.,Mai T.,Nair S.,et al. AP-1 is a temporally regulated dual gatekeeper of reprogramming to pluripotency[J],2021,118(23).
APA	Markov G.J..,Mai T..,Nair S..,Shcherbina A..,Wang Y.X..,...&Blau H.M..(2021).AP-1 is a temporally regulated dual gatekeeper of reprogramming to pluripotency.Proceedings of the National Academy of Sciences of the United States of America,118(23).
MLA	Markov G.J.,et al."AP-1 is a temporally regulated dual gatekeeper of reprogramming to pluripotency".Proceedings of the National Academy of Sciences of the United States of America 118.23(2021).