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Series GSE121052 Query DataSets for GSE121052
Status Public on May 21, 2021
Title AP-1 is a temporally regulated dual gatekeeper of reprogramming to pluripotency (RNA-Seq)
Organisms Homo sapiens; Mus musculus
Experiment type Expression profiling by high throughput sequencing
Summary 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. By ATAC-seq and ChIP-seq we identified enrichment for the 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 iPSC 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: i) to potentiate fibroblast enhancer accessibility and fibroblast-specific gene expression and ii) 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.
Overall design Human fibroblasts are fused with mouse embryonic stem cells (mESCs) with or without induction of dominant negative AP-1 (dnAP-1) to make heterokaryons. Heterokaryons are sorted at the specified timepoint post-fusion. Fibroblasts alone, fibroblasts co-cultured with mESCs (co-culture), and fibroblasts fused with each other (homokaryon) are used as controls. RNA is extracted for RNA-seq library preparation and sequencing.
Contributor(s) Markov GJ, Mai T, Nair S, Shcherbina A, Wang YX, Burns DM, Kundaje A, Blau HM
Citation(s) 34088849
NIH grant(s)
Grant ID Grant title Affiliation Name
R01 HG009674 Learning Regulatory Drivers of Chromatin and Expression Dynamics during Nuclear Reprogramming STANFORD UNIVERSITY HELEN M BLAU
Submission date Oct 10, 2018
Last update date Jun 06, 2021
Contact name Helen M Blau
Organization name Stanford University
Department Baxter Laboratories
Street address 269 Campus Dr
City Stanford
State/province CA
ZIP/Postal code 94305
Country USA
Platforms (2)
GPL18573 Illumina NextSeq 500 (Homo sapiens)
GPL19415 Illumina NextSeq 500 (Homo sapiens; Mus musculus)
Samples (27)
GSM5283121 RNA-Seq Fibroblast rep1
GSM5283122 RNA-Seq Fibroblast rep2
GSM5283123 RNA-Seq Fibroblast rep3
This SubSeries is part of SuperSeries:
GSE121053 AP-1 is a temporally regulated dual gatekeeper of reprogramming to pluripotency
BioProject PRJNA495468
SRA SRP164889

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Supplementary file Size Download File type/resource
GSE121052_Heterokaryon.hum.TPM.txt.gz 1.4 Mb (ftp)(http) TXT
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Raw data are available in SRA
Processed data are available on Series record

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