Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

AP-1 is a temporally regulated dual gatekeeper of reprogramming to pluripotency (ATAC-Seq)

ABSTRACT: 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.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE120992 | GEO | 2021/05/21

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

AP-1 is a temporally regulated dual gatekeeper of reprogramming to pluripotency (ChIP-Seq)

Project description: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.

2021-05-21 | GSE173937 | GEO

AP-1 is a temporally regulated dual gatekeeper of reprogramming to pluripotency (RNA-Seq)

2021-05-21 | GSE121052 | GEO

Chromatin Open/Close Logic in Cellular Reprogramming [ChIP-Seq]

Project description:The reprogramming of fibroblasts into pluripotent stem cells by Oct4, Sox2, Myc and Klf4 represents a unique system to understand the logic of cell fate decisions. The reprogramming process can be divided into initial, middle and maturation phases that are coupled to the ordered execution of multiple biological processes, of which one of the earliest is a mesenchymal to epithelial transition (MET). Yet, despite these critical insights, less is known about how the reprogramming factors alter the chromatin state to convert somatic cells back to pluripotent cells. Here we report the global chromatin accessibility dynamics as cells reprogram from a somatic to a pluripotent state as assessed by assay for transposase-accessible chromatin with sequencing (ATAC-seq). We show that chromatin changes during reprogramming are defined by a fast initial wave of chromatin changes from accessible/open to inaccessible/closed (OC), which is followed by a slower opening up of chromatin from closed to open (CO), and ends with a climactic wave of CO. The initial OC wave includes loci enriched with motifs for AP-1, TEAD, RUNX and ETS-family transcription factors. Consistently, over-expression of one of the AP-1-family members c-Jun, c-Fos and Fra1blocked reprogramming. c-Jun inhibits reprogramming by preventing OSK-driven OC and skewing the overall OC-CO dynamics. Paradoxically, we show that Sox2 and to a less extent Oct4 and Klf4 are CO-, not OC-, mediators , suggesting that they must first activate potent OC factors to remodel chromatin. Indeed, we show that Sap30, a component of the Sin3 complex8, functions as such an OC factor. Together, our results reveal the chromatin accessibility logic during reprogramming and identify Sap30 as one of the first responders that help silence somatic genes.

2017-12-09 | GSE98404 | GEO

Chromatin Open/Close Logic in Cellular Reprogramming [RNA-Seq]

2017-12-09 | GSE93027 | GEO

Chromatin Open/Close Logic in Cellular Reprogramming [ATAC-Seq]

2017-12-09 | GSE93026 | GEO

Retrospective identification of cell-intrinsic factors that mark pluripotency potential in rare somatic cells (scRNA-Seq)

Project description:Pluripotency can be induced in somatic cells by the expression of the four “Yamanaka” factors OCT4, KLF4, SOX2, and MYC. However, even in homogeneous conditions, usually only a rare subset of cells admit reprogramming, and the molecular characteristics of this subset remain unknown. Here, we apply retrospective clone tracing to identify and characterize the individual human fibroblast cells that are primed for reprogramming. These fibroblasts showed markers of increased cell cycle speed and decreased fibroblast activation. Knockdown of a fibroblast activation factor identified by our analysis led to increased reprogramming efficiency, identifying it as a barrier to reprogramming. Changing the frequency of reprogramming by inhibiting the activity of LSD1 led to an enlarging of the pool of cells that were primed for reprogramming. Our results show that even homogeneous cell populations can exhibit heritable molecular variability that can dictate whether individual rare cells will reprogram or not.

2023-03-11 | GSE227151 | GEO

Retrospective identification of cell-intrinsic factors that mark pluripotency potential in rare somatic cells (RNA-seq)

2023-03-11 | GSE226987 | GEO

Retrospective identification of cell-intrinsic factors that mark pluripotency potential in rare somatic cells

2023-09-25 | GSE243933 | GEO

Deterministic direct reprogramming of somatic cells to pluripotency [Microarray/Expression]

Project description:Somatic cells can be directly reprogrammed to pluripotency by exogenous expression of transcription factors, classically Oct4, Sox2, Klf4 and c-Myc. While distinct types of somatic cells can be reprogramed with varying efficiencies and by different modified reprogramming protocols, induced pluripotent stem cell (iPSC) induction remains inefficient and stochastic where a fraction of the cells converts into iPSCs. The nature of rate limiting barrier(s) preventing majority of cells to convert into iPSCs remains elusive. Here we show that neutralizing Mbd3, a core member of the Mbd3/NURD co-repressor and chromatin-remodeling complex, results in deterministic and synchronized reprogramming of multiple differentiated cell types to pluripotency. 100% of Mbd3 depleted mouse and human somatic cells convert into iPSCs after seven days of reprogramming factor induction. Our findings delineate a critical pathway blocking the reestablishment of pluripotency, and offer a novel platform for future dissection of epigenetic dynamics leading to iPSC formation at high resolution. Samples include Mbd3+/+, Mbd3flox/- and Mbd3-/- cells from mouse ES cells and mouse embryonic fibroblast (MEF) before and after DOX induction (initiating reprogramming by OSKM factors).

2013-09-12 | E-GEOD-45352 | biostudies-arrayexpress

Molecular insights into induced pluripotency mediated by the OCT4, SOX2, KLF and c-MYC gene regulatory network

Project description:Human somatic fibroblasts can be reprogrammed to induced pluripotent stem (iPS) cells by exogenic expression of the Yamanaka factors (OCT4, SOX2, KLF4 and MYC) after about 1 month. To gain some insight into the early processes operative in fibroblast reprogramming, we profiled genome-wide transcription levels using Illumina microarrays in the starting donor cells-human foreskin fibroblast (HFF1) cells and at three time points after OSKM transduction (24 h, 48 h, 72 h), as well as two iPS cell lines (iPS2, iPS4) and hES cell lines (H1, H9). We show that within the context of the viral transduction reprogramming protocol, the donor cell response to viral transfection perturbs redox homeostasis, which induces oxidative damage on the donor cells' protein and DNA. This leads to activation of p53, senescence, and apoptosis, greatly reducing the efficiency of reprogramming. Total RNA obtained from HFF1 (human foreskin fibroblast) cells, OSKM-transduced HFF1 cells after 24h, 48h, 72h, undifferentiated hESCs, iPSCs.

2011-10-24 | E-GEOD-28688 | biostudies-arrayexpress

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data