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Permissive epigenomic states endow reprogramming competence to a broad range of transcriptional regulators

ABSTRACT: Identifying molecular targets that regulate reprogramming competence of transcription factors in donor cells broadens our understanding of reprogramming process. Here, by a chemical screen targeting major epigenetic pathways in human reprogramming, we discovered that inhibiting specific epigenetic roadblocks allows iPSC generation with almost all OCT factors. Amongst these epigenetic pathways was not only DOT1L-mediated H3K79 methylation but also other modifications catalyzed by LSD1, DNMTs and HDACs, and we found that simultaneous inhibition of these pathways not only dramatically enhances reprogramming competence of most OCT factors but in fact enables to dismantle species-dependent reprograming competence of OCT6, NR5A1, NR5A2, TET1 and GATA3. Harnessing these permissive epigenetic states, we performed an additional screen with 98 transcriptional regulators. Thereby, we identified 25 novel genes that can functionally replace OCT4 in inducing pluripotency. Our findings provide a conceptional framework for understanding how transcription factors elicit reprogramming in dependency of the donor cell epigenome that differs across species.

ORGANISM(S): Homo sapiens

PROVIDER: GSE149017 | GEO | 2020/06/24

REPOSITORIES: GEO

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Reprogramming competence of POU factors is linked to the donor-cell epigenome

Project description:Octamer-binding Pit-Oct-Unc (POU) family members have distinct reprogramming competences. OCT4 induces pluripotency, whereas POU III factors (OCT6, OCT7, OCT8, and OCT9) lack this ability, but are prone to inducing neural identities. However, which specific features of these proteins render the distinct reprograming competences remains unknown. Here, we present that OCT6 can also induce pluripotency. But, it works only with human cells, indicating its species-dependent reprogramming activity. Functional readouts with a series of reciprocal mutants uncover that the central role of OCT4 and its strong reprogramming competence to pluripotency arise from its C-terminal transactivation domain. Furthermore, we identify intrinsic properties of OCT7, OCT8, and OCT9 that are detrimental for inducing pluripotency. A chemical screen reveals that their persistent deficiency for inducing pluripotency can be surmounted by reducing H3K79 methylation in donor cells. Our findings delineate that intrinsic properties of POU factors and their responsive donor-cell epigenome state are tightly linked to the reprogramming competence.

2020-06-24 | GSE95608 | GEO

OCT6 uniquely replaces OCT4 in inducing human pluripotency

Project description:Somatic cells can be reprogrammed into pluripotent stem cells by the ectopic expression of OCT4, SOX2, KLF4, and c-MYC. Although SOX2, KLF4, and c-MYC (SKM) can be substituted by their respective family members, OCT4 is considered to not be interchangeable with any octamer-binding POU proteins. Through a screening with 102 candidate genes, here we have identified that the POU protein OCT6 (also known as SCIP, TST-1, and POU3F1), in conjunction with SKM, is capable of functionally replacing OCT4 and inducing pluripotency. OCT6-mediated reprogramming works with any human cell type, but not with mouse cells. The reprogramming process involving OCT6 is relatively inefficient and slow. This is mainly due to either inefficient formation of OCT6-SOX2 heterodimers onto canonical SOX-OCT sites or lower transactivation activity of OCT6. We demonstrate that modulating either the DNA-binding propensity or the transactivation activity of OCT6 enhances iPSC generation to the efficiency of OCT4. These results thus provide the first evidence that a POU factor other than OCT4 can induce human pluripotency.

2019-01-17 | GSE93706 | GEO

Reprogramming competence of POU factors is linked to the donor-cell epigenome

Project description:Reprogramming competence of POU factors is linked to the donor-cell epigenome

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Pluripotency reprogramming by competent and incompetent POU factors uncovers temporal dependency for Oct4 and Sox2 [ATAC-Seq]

Project description:Oct4, along with Sox2 and Klf4 (SK), can induce pluripotency but structurally similar factors like Oct6 cannot. To decode why Oct4 has this unique ability, we compare Oct4-binding, accessibility patterns and transcriptional waves with Oct6 and an Oct4 mutant defective in the dimerization with Sox2 (Oct4defSox2). We find that initial silencing of the somatic program proceeds indistinguishably with or without Oct4. Oct6 mitigates the mesenchymal-to-epithelial transition and derails reprogramming. These effects are a consequence of differences in genome-wide binding, as the early binding profile of Oct4defSox2 resembles Oct4, whilst Oct6 does not bind pluripotency enhancers. Nevertheless, in the Oct6-SK condition many otherwise Oct4-bound locations become accessible but chromatin opening is compromised when Oct4defSox2 occupies these sites. We find that Sox2 predominantly facilitates chromatin opening, whilst Oct4 serves an accessory role. Formation of Oct4/Sox2 heterodimers is essential for pluripotency establishment; however, reliance on Oct4/Sox2 heterodimers declines during pluripotency maintenance.

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Pluripotency reprogramming by competent and incompetent POU factors uncovers temporal dependency for Oct4 and Sox2

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Pluripotency reprogramming by competent and incompetent POU factors uncovers temporal dependency for Oct4 and Sox2 [RNA-Seq]

2019-06-18 | GSE103979 | GEO

Pluripotency reprogramming by competent and incompetent POU factors uncovers temporal dependency for Oct4 and Sox2 [CHIP-Seq]

2019-06-18 | GSE103978 | GEO

Oct6 promotes neural commitment via activation of neural lineage genes and inhibition of BMP/Wnt signals

Project description:The neural fate commitment of pluripotent stem cells requires repression of extrinsic inhibitory signals and activation of intrinsic positive transcription factors. However, it remains elusive how these two events are integrated to ensure appropriate neural conversion. Here, we show that Oct6 functions as an essential positive factor for neural differentiation of mouse embryonic stem cells (ESCs), specifically during the transition from epiblast stem cells (EpiSCs) to neural progenitor cells (NPCs). Chimera analysis showed that Oct6 knockdown leads to markedly decreased incorporation of ESC in neuroectoderm. By contrast, Oct6-overexpressing ESC derivatives preferentially contribute to neuroectoderm. Genome-wide ChIP-seq and RNA-seq analyses indicate that Oct6 is an upstream activator of neural lineage genes, and also a repressor of BMP and Wnt signalings. Our results establish Oct6 as a critical regulator that promotes neural commitment of pluripotent stem cells through a dual role: activating internal neural induction programs and antagonizing extrinsic neural inhibitory signals. RNA-seq was performed to examine Oct6 function in ESC neural differentiation at Day2, Day4 and Day6 after dox induction. On Day4 EB, ChIP-seq assay was ultilized to characterize the targets of Oct6.

2014-01-31 | E-GEOD-54569 | biostudies-arrayexpress

Induced Pluripotent Mesenchymal Stromal Cell Clones Retain Donor-Derived Differences in DNA Methylation Profiles

Project description:Reprogramming of somatic cells into induced pluripotent stem cells (iPSC) is an epigenetic phenomenon. It has been suggested that iPSC retain some tissue-specific memory whereas little is known about inter-individual epigenetic variation of iPSC clones. In this study we have reprogrammed mesenchymal stromal cells (MSC) from human bone marrow by retrovirus-mediated overexpression of OCT-3/4, SOX2, c-MYC, and KLF4. Global DNA-methylation profiles of the initial MSC, MSC-derived iPSC (iP-MSC) and embryonic stem cells (ESC) were then compared using a high density DNA-methylation array covering more than 450,000 CpG sites. Overall, DNA-methylation patterns of iP-MSC and ESC were similar whereas some CpG sites revealed highly significant differences, which were not related to parental MSC. Furthermore, hypermethylation in iP-MSC versus ESC was particularly enriched in developmental genes as well as shore regions next to CpG islands indicating that these differences are not due to tissue-specific memory or random de novo methylation. Subsequently, we searched for CpG sites with donor-specific variation in MSC preparations. These “epigenetic fingerprints” were highly enriched in non-promoter regions and outside of CpG islands – and they were maintained upon reprogramming into iP-MSC. In conclusion, DNA methylation profiles of iP-MSC clones from the same donor were closely related despite heterogeneity of MSC. On the other hand, iP-MSC maintain donor-derived epigenetic differences. In the absence of isogenic controls for disease modeling applications, it would therefore be more appropriate to compare iPSC from different donors rather than a high number of different clones from the same patient. 16 samples were hybridised to the Illumina Infinium 450k Human Methylation Beadchip

2013-01-09 | E-GEOD-34688 | biostudies-arrayexpress

Selective influence of Sox2 on POU transcription factor binding in embryonic and neural stem cells

Project description:Embryonic stem cell (ESCs) identity is orchestrated by co-operativity between the transcription factors (TFs) Sox2 and the class V POU-TF, Oct4 at composite Sox/Oct motifs. Neural stem cells (NSCs) lack Oct4 but express Sox2 and class III POU-TFs. This raises the question of how Sox2 interacts with POU-TFs to transcriptionally specify ESCs or NSCs. Here we show that Oct4 alone binds the Sox/Oct motif and the octamer-containing palindromic MORE equally well. Sox2 binding selectively increases the affinity of Oct4 for the Sox/Oct motif. In contrast, Oct6 binds preferentially to the MORE, and is unaffected by Sox2. ChIP-seq in NSCs shows the MORE to be the most enriched motif for class III POU-TFs, with MORE sub-types apparent, but no Sox/Oct motif enrichment. These results suggest that in NSCs, co-operativity between Sox2 and class III POU-TFs may not occur and that POU-TF driven transcription uses predominantly the MORE cis architecture. Thus, distinct interactions between Sox2 and POU-TF subclasses distinguish pluripotent ESCs from multipotent NSCs, providing molecular insight into how Oct4 alone can convert NSCs to pluripotency.

2015-08-21 | GSE69859 | GEO

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