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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE72741 | GEO | 2015/12/10

SECONDARY ACCESSION(S): PRJNA294797

REPOSITORIES: GEO

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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

The histone chaperone CAF-1 safeguards somatic cell identity during transcription factor-induced reprogramming (sequencing)

Project description:During development, specialized cell lineages are generated through the establishment of cell type-specific transcriptional patterns and epigenetic programs. However, the precise mechanisms and regulators that maintain these specialized cell states remain largely elusive. To identify molecules that safeguard somatic cell identity, we performed two comprehensive RNAi screens targeting known and predicted chromatin regulators 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, DNA methylation and heterochromatin maintenance. Suppression of CAF-1 increased reprogramming efficiencies by several orders of magnitude and generated iPSCs two to three times faster compared to controls without affecting cell proliferation. We demonstrate that suppression of CAF-1 leads to a more accessible chromatin structure specifically at enhancer elements early during reprogramming. These changes were accompanied by increased binding of the reprogramming factor Sox2 to ESC-specific regulatory elements and earlier activation of pluripotency-associated genes. Notably, suppression of CAF-1 also enhanced iPSC formation from blood progenitors as well as the direct conversion of B cells into macrophages and fibroblasts into neurons. Together, our findings reveal the histone chaperone CAF-1 as an unanticipated regulator of somatic cell identity and provide a potential strategy to modulate cellular plasticity in a regenerative setting. Keywords: Genome binding/occupancy profiling by high throughput sequencing Chromatin accessibility and Sox2 bindings in CAF-1 knockdown and Renilla control during early OKSM reprogramming by high throughput sequencing

2015-12-10 | E-GEOD-72744 | biostudies-arrayexpress

The histone chaperone CAF-1 safeguards somatic cell identity during transcription factor-induced reprogramming (sequencing)

2015-12-10 | GSE72744 | GEO

Mus musculus

Project description:CAF-1 safeguards somatic cell identity during factor-induced reprogramming

| PRJNA294797 | ENA

BRD9-containing non-canonical BAF chromatin remodeling complex acts as a barrier to somatic cell reprogramming (ATAC-Seq)

Project description:Epigenetic reprogramming requires extensive remodeling of chromatin landscapes to silence gene expression programs which sustain cell identity. ATP-dependent chromatin-remodeling complexes are important regulators of chromatin structure and gene expression; however, the role of Bromodomain containing protein 9 (BRD9) and the associated ncBAF (non-canonical BRG1-associated factors) complex in somatic cell reprogramming remains unknown. Here, we show that inhibition and acute degradation of BRD9 increases the efficiency by which induced pluripotent stem cells (iPSCs) can be generated from human fibroblasts. Genetic suppression of BRD9 as well as ncBAF complex subunit GLTSCR1, but not the closely related BRD7, phenocopied this effect. CRISRP/Cas9-mediated knockout of BRD9 demonstrated that it is dispensable for establishment and maintenance of human pluripotency. Mechanistically, BRD9 inhibition facilitates reprogramming by downregulating somatic cell type-specific genes and decreasing chromatin accessibility at somatic enhancers. Collectively, these results establish BRD9 as an important safeguarding factor for somatic cell identity whose inhibition lowers barriers to reprogramming.

2021-06-15 | GSE161639 | GEO

BRD9-containing non-canonical BAF chromatin remodeling complex acts as a barrier to somatic cell reprogramming (RNA-Seq)

2021-06-15 | GSE161637 | GEO

Project description:The histone chaperone CAF-1 safeguards somatic cell identity during transcription factor-induced reprogramming

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Nudt21 controls cell fate by connecting alternative polyadenylation to chromatin signaling

Project description:Cell fate transitions involve rapid changes of gene expression patterns and global chromatin remodeling, yet the underlying regulatory pathways remain incompletely understood. Here, we used transcription-factor induced reprogramming of somatic cells into pluripotent cells to screen for novel regulators of cell fate change. We identified the RNA processing factor Nudt21, a component of the pre-mRNA cleavage and polyadenylation complex, as a potent barrier to reprogramming. Importantly, suppression of Nudt21 not only enhanced the generation of induced pluripotent stem cells but also facilitated the conversion of fibroblasts into trophoblast stem cells and delayed the differentiation of myeloid precursor cells into macrophages, suggesting a broader role for Nudt21 in restricting cell fate change. Polyadenylation site sequencing (PAS-seq) revealed that Nudt21 directs differential polyadenylation of over 1,500 transcripts in cells acquiring pluripotency. While only a fraction of these transcripts changed expression at the protein level, this fraction was strongly enriched for chromatin regulators, including components of the PAF, polycomb, and trithorax complexes. Co-suppression analysis further suggests that these chromatin factors are largely responsible for Nudt21’s effect on reprogramming, providing a mechanistic basis for our observations. Collectively, our data uncover Nudt21 as a novel post-transcriptional regulator of mammalian cell fate and establish a direct, previously unappreciated link between alternative polyadenylation and chromatin signaling.

2018-01-08 | PXD008078 | Pride

Widespread targeted chromatin remodeling during the initial phase of somatic cell reprogramming [expression]

Project description:Despite rapid progress in characterizing transcription factor-driven reprogramming of somatic cells to an induced pluripotent stem (iPS) cell state, many mechanistic questions still remain. To gain insight into the earliest events in the reprogramming process, we systematically analyzed the transcriptional and epigenetic changes that occur during early factor induction after discrete numbers of divisions. We observed rapid, genome-wide changes in the euchromatic histone modification, H3K4me2, at more than a thousand loci including large subsets of pluripotency or developmentally related gene promoters and enhancers. In contrast, patterns of the repressive H3K27me3 modification remained largely unchanged except for focused depletion specifically at positions where H3K4 methylation is gained. These chromatin regulatory events precede transcriptional changes within the corresponding loci. Our data provide evidence for an early, organized, and population-wide epigenetic response to ectopic reprogramming factors that clarify the temporal order through which somatic identity is reset during reprogramming. Gene expression was measured by Affymetric microarrays during the initial phase of the reprogramming of mouse embryonic fibroblasts.

2011-01-03 | E-GEOD-26096 | biostudies-arrayexpress

CAF-1 Histone Chaperone is a Repressor of Mixed Cellular States in Myeloid Progenitors [scRNA-seq]

Project description:To characterize the cell identity of CAF-1 depleted Hoxa9-granulocyte-macrophage progenitors (Hoxa9-GMPs) and address whether CAF-1 suppression in Hoxa9-GMPs leads to either a heterogeneous or a mixed lineage state, we conducted single cell transcriptome analysis before and after the Hoxa9-GMPs commit to differentiation in both CAF-1 suppression and Hoxa9 inactivation conditions.

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