Heterochromatin lossening by Oct4 in somatic cell reprogramming
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ABSTRACT:
PROVIDER: PRJNA532597 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8889400_1.fastq.gz | Fastqsanger.gz | |||
| SRR8889400_2.fastq.gz | Fastqsanger.gz | |||
| SRR8889410_1.fastq.gz | Fastqsanger.gz | |||
| SRR8889410_2.fastq.gz | Fastqsanger.gz | |||
| SRR8889391_1.fastq.gz | Fastqsanger.gz |
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Project description:OCT4 is expressed in extraembryonic endoderm stem (XEN) cell progenitors during somatic cell reprogramming
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Project description:Forced expression of four transcription factors Oct4,Sox2, Klf4 and Myc (OSKM) induces somatic cell reprogramming towards pluripotency. Major efforts have been made to characterize the molecular events involved in this process. Yet, it remains elusive how gene expression change, epigenetic landscape remodelling and cell fate conversion are triggered by expression of these Yamanaka factors.To address this gap,we utilized a secondary inducible reprogramming system and performed genome-wide profilings of Oct4 binding, histone modification(H3K4me3/H3K27me3/H3K4me1/H3K27ac), and gene expression analysis during this process. Through integrative analysis, we revealed stage-specific Oct4 binding and enhancer signatures in consistence with gene expression changes,in which the initial regression of somatic program is followed by the gradual acquisition of pluripotent program. Oct4 preferatially binds to H3K4me1 marked enhancer regions and Oct4 binding is positively correlated with active mark H3K27ac. Moreover,we observed significant enhancer activation of epigenetic related genes, especially acetylation associated genes, prior to pluripotency network activation, suggesting a pivotal role of epigenetic remodelling in the process of pluripotency acquisition and maintenance. We used ChIP-seq to explore the global changes of Oct4 binding profiling during OSKM-mediated somatic cell reprogramming. The exogenous Oct4 was tagged with 3XFlag, thus we used anti-flag antibody to monitor exogenous Oct4 changes; anti-Oct4 antibody which recognizes both endogenous and exogenous Oct4 was used to monitor total Oct4 changes during iPSC induction. In addition, we also examined genome-wide H3K4me1/H3K27ac/H3K4me3/H3K27me3/RNAPII profiling during 3Flag-OSKM 2' reprogramming.
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Project description:During development, progenitors of embryonic stem (ES) and extraembryonic endoderm stem (XEN) cells are concomitantly specified within the inner cell mass (ICM) of the mouse blastocyst. Similarly, XEN cells are induced (iXEN cells) alongside induced pluripotent stem (iPS) cells following overexpression ofOct4,Sox2,Klf4andMyc(OSKM) during somatic cell reprogramming. It is unclear how or why this cocktail produces both stem cell types, but OCT4 has been associated with non-pluripotent outcomes. In this report, we show that, during OSKM reprogramming, many individualOct4-GFP-expressing cells are fated to become iXEN cells. Interestingly, SKM alone was also sufficient to induce iXEN cell formation, likely via activation of endogenousOct4.These observations indicate that iXEN cell formation is not strictly an artifact ofOct4overexpression. Moreover, our results suggest that a pathway to XEN may be an integral feature of establishing pluripotency during reprogramming, as in early embryo development.
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Project description:Cellular differentiation involves profound changes in the chromatic landscape, yet the mechanisms by which somatic cell identity is subsequently maintained remain incompletely understood. To further elucidate regulatory pathways that safeguard the somatic state, we performed two comprehensive RNAi screens targeting chromatin factors during transcription factor-mediated reprogramming of mouse fibroblasts to induced pluripotent stem cells (iPSCs). Remarkably, subunits of the chromatin assembly factor-1 (CAF-1) complex emerged as the most prominent hits from both screens, followed by modulators of lysine sumoylation and heterochromatin maintenance. Suppression of CAF-1 increased reprogramming efficiency by several orders of magnitude and facilitated iPSC formation in as little as 4 days. Mechanistically, CAF-1 suppression led to a more accessible chromatin structure at enhancer elements early during reprogramming. These changes were accompanied by a decrease in somatic heterochromatin domains, increased binding of Sox2 to pluripotency-specific targets and activation of associated genes. Notably, suppression of CAF-1 also enhanced the direct conversion of B cells into macrophages and fibroblasts into neurons. Together, our findings reveal the histone chaperone CAF-1 as a novel regulator of somatic cell identity during transcription factor-induced cell fate transitions and provide a potential strategy to modulate cellular plasticity in a regenerative setting. Gene expression analysis in CAF-1 knockdown and Renilla control during early OKSM-induced reprogramming by microarray
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Project description:Amongst the multiple cell fates orchestrated by OCT4, its ability to maintain pluripotency is thought to underpin reprogramming. How OCT4 drives pluripotency from diverse cellular contexts is unclear. By systematically dissecting OCT4, we find that reprogramming requires OCT4 domains dispensable for pluripotency maintenance and development throughout gastrulation but important for the embryo competence to develop through late gestation. Removing OCT4 essential domains in reprogramming leads to more non-specific OCT4 enrichment at accessible somatic sites, unlike removing the non-essential domains, which expands genomic targeting of closed pluripotency sites. Delineating the interaction of OCT4 with chromatin-associated proteins in reprogramming and pluripotency maintenance reveals that OCT4 essential domains engage a unique set of proteins during reprogramming. Remarkably, OCT4 can induce pluripotent and trophoblast stem cells using many similar domains and yet it can be truncated to only induce pluripotency. Our findings demonstrate that the ability of transcription factors to control diverse cell types is encoded within their modular nature.
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Project description:Amongst the multiple cell fates orchestrated by OCT4, its ability to maintain pluripotency is thought to underpin reprogramming. How OCT4 drives pluripotency from diverse cellular contexts is unclear. By systematically dissecting OCT4, we find that reprogramming requires OCT4 domains dispensable for pluripotency maintenance and development throughout gastrulation but important for the embryo competence to develop through late gestation. Removing OCT4 essential domains in reprogramming leads to more non-specific OCT4 enrichment at accessible somatic sites, unlike removing the non-essential domains, which expands genomic targeting of closed pluripotency sites. Delineating the interaction of OCT4 with chromatin-associated proteins in reprogramming and pluripotency maintenance reveals that OCT4 essential domains engage a unique set of proteins during reprogramming. Remarkably, OCT4 can induce pluripotent and trophoblast stem cells using many similar domains and yet it can be truncated to only induce pluripotency. Our findings demonstrate that the ability of transcription factors to control diverse cell types is encoded within their modular nature.
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