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Tox4 Modulates Cell Fate Reprogramming

ABSTRACT: Reprogramming to induced pluripotency induces the switch of somatic cell identity to induced pluripotent stem cells (iPSCs). However, the mediators and mechanisms of reprogramming remain largely unclear. To elucidate the mediators and mechanisms of reprogramming, we used a siRNA mediated knockdown approach for selected candidate genes during the conversion of somatic cells into iPSCs. We identified Tox4 as a novel factor that modulates cell fate, using reprogramming efficiency towards iPSCs as an assay. We found that Tox4 is needed early in reprogramming to efficiently generate early reprogramming intermediates, irrespective of reprogramming conditions used. Tox4 enables proper exogenous reprogramming factor expression and the closing and opening of putative somatic and pluripotency enhancers early during reprogramming, respectively. We show that TOX4 protein assembles into a high molecular form. Moreover, Tox4 is also required for the efficient conversion of fibroblasts towards the neuronal fate, suggesting a broader role of Tox4 in modulating cell fate. Our study reveals Tox4 as a novel transcriptional modulator of cell fate that mediates reprogramming from the somatic state to the pluripotent and neuronal fate.

ORGANISM(S): Mus musculus

PROVIDER: GSE127932 | GEO | 2019/09/19

REPOSITORIES: GEO

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Tox4 Modulates Cell Fate Reprogramming

Project description:Reprogramming to induced pluripotency induces the switch of somatic cell identity to induced pluripotent stem cells (iPSCs). However, the mediators and mechanisms of reprogramming remain largely unclear. To elucidate the mediators and mechanisms of reprogramming, we used a siRNA mediated knockdown approach for selected candidate genes during the conversion of somatic cells into iPSCs. We identified Tox4 as a novel factor that modulates cell fate, using reprogramming efficiency towards iPSCs as an assay. We found that Tox4 is needed early in reprogramming to efficiently generate early reprogramming intermediates, irrespective of reprogramming conditions used. Tox4 enables proper exogenous reprogramming factor expression and the closing and opening of putative somatic and pluripotency enhancers early during reprogramming, respectively. We show that TOX4 protein assembles into a high molecular form. Moreover, Tox4 is also required for the efficient conversion of fibroblasts towards the neuronal fate, suggesting a broader role of Tox4 in modulating cell fate. Our study reveals Tox4 as a novel transcriptional modulator of cell fate that mediates reprogramming from the somatic state to the pluripotent and neuronal fate.

2019-09-19 | GSE127930 | GEO

Tox4 Modulates Cell Fate Reprogramming

Project description:Tox4 Modulates Cell Fate Reprogramming

| PRJNA525830 | ENA

Tox4 Modulates Cell Fate Reprogramming

Project description:Tox4 Modulates Cell Fate Reprogramming

| PRJNA525831 | ENA

CAF-1 safeguards somatic cell identity during factor-induced reprogramming

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

2015-12-10 | E-GEOD-72741 | biostudies-arrayexpress

Tox4 Modulates Cell Fate Reprogramming to iPS Cells and Direct Reprogramming

Project description:Tox4 Modulates Cell Fate Reprogramming to iPS Cells and Direct Reprogramming

| PRJNA525829 | ENA

Amphiregulin mediates non-cell-autonomous effect of senescence on reprogramming

Project description:Cellular senescence is an irreversible growth arrest with a highly dynamic secretome, termed the senescence-associated secretory phenotype (SASP). Senescence has been implicated in somatic reprogramming to pluripotency. The cell-intrinsic proliferation arrest is a barrier for reprogramming, whereas the SASP facilitates the cell fate conversion in nonsenescent cells. However, the mechanisms by which reprogramming-induced senescence regulates cell plasticity are not well understood. Here, we have further investigated how the heterogeneity of paracrine senescence impacts reprogramming. We show that senescence promotes in vitro reprogramming in a stress-dependent manner. We identified a catalog of SASP factors and pathways potentially involved in the cell fate conversion using an unbiased proteomic analysis. Amphiregulin (AREG), a growth factor frequently secreted by the senescent cells, promotes in vitro reprogramming by accelerating proliferation and MET via the EGFR signaling pathway. Of note, AREG treatment diminished the negative effect of donor age on reprogramming. Finally, AREG enhances in vivo reprogramming in the skeletal muscle. Hence, senescence could facilitate cellular plasticity via various SASP factors to promote reprogramming and tissue repair.

2022-07-28 | PXD028590 | Pride

Tet1 as a Negative Regulator of Somatic Cell Reprogramming

Project description:Tet1 is a hydroxylase known for its role in the conversion of 5-methylcytosines (5mC) to 5-hydroxymethylcytosines (5hmC) involved in the possible active demethylation process and gene expression regulation1-5.M-BM- As somatic cell reprogramming involves the re-activation of pluripotency genes and the silencing of somatic ones6, it remains unclear whether Tet1 plays a positive or negative role in the reprogramming process. Here we show that Tet1 deficiency enhances reprogramming and its overexpression impairs reprogramming. Mechanistically, we demonstrated that Tet1 represses the early obligatory process of mesenchymal to epithelial transition (MET) during reprogramming7,8. Thus, our findings not only define a negative role for Tet1 in somatic cell reprogramming, but also suggest that the Tet enzymes regulate cell fate through distinctive mechanisms. Examination of genome DNA hmC modifications in 2 conditions: individually overexpressed Tet1CD or Tet2CD during MEF reprogramming; Examination of mRNA levels in five different conditions: individually overexpressed DR or Tet1CD or Tet1CDmut or Tet2CD or Tet2CDmut, during MEF reprogrammig.

2013-03-08 | E-GEOD-44935 | biostudies-arrayexpress

Reprogramming by de-bookmarking somatic transcriptional program via targeting the BET bromodomains

Project description:One critical task in pluripotent reprogramming is to erase the somatic transcriptional program of starting cells. No strategy or theory exists for achieving erasure of somatic gene expression memory. Here, we present a proof-of-principle strategy in which reprogramming to pluripotency is facilitated by small molecules that erase somatic cell transcription memory. We show that mild chemical targeting of the acetyllysine-binding pockets of the BET bromodomains, the transcriptional bookmarking domains, robustly enhances reprogramming. Furthermore, we show that chemical targeting of the transcriptional bookmarking BET bromodomains dramatically downregulates specific somatic gene expression programs in both naÃ¯ve and reprogramming fibroblasts. Chemical blocking of the BET bromodomains also resulted in loss of fibroblast morphology early in reprograming. In this study, we experimentally demonstrate a concept for cell fate conversion: facilitating the conversion by chemically targeting the transcriptional bookmarking BET bromodomains responsible for transcriptional memory. human BJ cells were treated with JQ1 at 50 nM for 48 hours. Differential expression was compared with DMSO treatment. The same treatments and comparsion were conducted for reprogramming BJ cells, which were transduced with OCT4, SOX2, and KLF4. JQ1iPSC5 is a iPSC (induced pluripotent stem cell) line generated in this study using small molecules JQ1.

2016-08-22 | E-GEOD-75364 | biostudies-arrayexpress

Reprogramming by de-bookmarking somatic transcriptional program via targeting the BET bromodomains

Project description:One critical task in pluripotent reprogramming is to erase the somatic transcriptional program of starting cells. No strategy or theory exists for achieving erasure of somatic gene expression memory. Here, we present a proof-of-principle strategy in which reprogramming to pluripotency is facilitated by small molecules that erase somatic cell transcription memory. We show that mild chemical targeting of the acetyllysine-binding pockets of the BET bromodomains, the transcriptional bookmarking domains, robustly enhances reprogramming. Furthermore, we show that chemical targeting of the transcriptional bookmarking BET bromodomains dramatically downregulates specific somatic gene expression programs in both naïve and reprogramming fibroblasts. Chemical blocking of the BET bromodomains also resulted in loss of fibroblast morphology early in reprograming. In this study, we experimentally demonstrate a concept for cell fate conversion: facilitating the conversion by chemically targeting the transcriptional bookmarking BET bromodomains responsible for transcriptional memory.

2016-08-22 | GSE75364 | GEO

Gene Expression Profile for knocking down Tet1 in pre-iPSCs culturing in Vc medium.

2013-10-27 | E-GEOD-48206 | biostudies-arrayexpress

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