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BMP4 Resets Primed to Naive Pluripotency by Reprogramming Chromatin Accessibility [RNA-Seq]

ABSTRACT: Mouse naive and primed pluripotent stem cells, ESC and EpiSC, represent two distinct stages of pluripotency. Here we report that BMP4 drives primed to naive transition or PNT by reprogramming chromatin accessibility. ATAC-seq reveals that a short pulse of BMP4 triggers EpiSCs to close 26409 and open 6428 loci to reach an intermediate state that continue to open 18744 and close 7042 loci under 2iL until reaching a naive state, following with a dramatic reactivation of the silenced X chromosome. Among loci opened by BMP4 are those encoding Id1, Tfap2c/2a and Zbtb7b that synergistically drive PNT without BMP4. Tfap2c-/- ESCs or EpiSCs self-renew normally, while the former capable of differentiating to the latter but the latter fails to undergo PNT, a defect rescuable by exogenous Tfap2c. Our results link BMP4 to PNT through a binary logic of chromatin closing and opening, revealing the intrinsic power of extracellular factors to reorganize nuclear architecture in development.

ORGANISM(S): Mus musculus

PROVIDER: GSE122936 | GEO | 2020/06/16

REPOSITORIES: GEO

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BMP4 Resets Primed to Naive Pluripotency by Reprogramming Chromatin Accessibility [ATAC-Seq]

Project description:Mouse naive and primed pluripotent stem cells, ESC and EpiSC, represent two distinct stages of pluripotency. Here we report that BMP4 drives primed to naive transition or PNT by reprogramming chromatin accessibility. ATAC-seq reveals that a short pulse of BMP4 triggers EpiSCs to close 26409 and open 6428 loci to reach an intermediate state that continue to open 18744 and close 7042 loci under 2iL until reaching a naive state, following with a dramatic reactivation of the silenced X chromosome. Among loci opened by BMP4 are those encoding Id1, Tfap2c/2a and Zbtb7b that synergistically drive PNT without BMP4. Tfap2c-/- ESCs or EpiSCs self-renew normally, while the former capable of differentiating to the latter but the latter fails to undergo PNT, a defect rescuable by exogenous Tfap2c. Our results link BMP4 to PNT through a binary logic of chromatin closing and opening, revealing the intrinsic power of extracellular factors to reorganize nuclear architecture in development.

2020-06-16 | GSE122935 | GEO

Evidence that c-JUN stabilizes chromatin architecture of EpiSCs

Project description:c-JUN is a transcription factor and the founding member of AP1 family. Here we present evidence that c-JUN stabilizes chromatin architecture. We first show that c-JUN is expressed and occupies chromatin loci both open and closed in primed mEpiSCs, but not naive mESCs. Interestingly, naive open loci undergo closing during naive to primed transition independent of c-JUN, but ~2500 of them become occupied by c-JUN immediately. These loci then open more readily during the reverse primed to naive transition (PNT) in the presence of c-JUN N-terminal Kinase inhibitor or by ectopically expressed Esrrb and Klf4 as both bind to them. Finally, we show that these loci become more open in c-Jun-/- EpiSCs which undergo PNT more efficiently than wild type cells. These results suggest that c-Jun is activated during naive to primed transition to stabilize chromatin architecture.

2022-12-24 | GSE192650 | GEO

BMP4 Resets Primed to Naive Pluripotency by Reprogramming Chromatin Accessibility [ChIP-Seq]

Project description:BMP4 regulates a plethora of developmental processes including dorsal-ventral axis and neural patterning. Here we report that BMP4 reconfigures nuclear archi-tecture during primed to naive transition (PNT). We first established a robust BMP4 driven PNT and shown by ATAC- and RNA-seq that it orchestrates the chromatin accessibility dynamics during PNT. Among the loci opened early by BMP4, we identified Zbtb7a/b as new targets that contribute to drive PNT. Mechanically, BMP first activates Zbtb7a/b in both chromatin and gene expression level, which in turn facilitate the opening of naïve pluripotent chromatin loci and allow the activation of naïve pluripotent genes. Surprisingly, Zbtb7a not only binds to chromatin loci near the genes to be activated, but also strategically occupies those to be silenced, thus resolving the conflicting role of BMP4 in both activating and suppressing gene ex-pression during PNT at the chromatin level. Our results reveal a previously un-known function of BMP4 in regulating nuclear architecture and link its targets Zbtb7a/b to chromatin remodeling and pluripotent fate control.

2020-06-16 | GSE146653 | GEO

c-JUN is a pioneer factor safeguarding the primed state of pluripotency (RNA-Seq)

Project description:Mouse ESCs and EpiSCs represent naive and primed states of plurioptency corresponding to two consecutive stages of embryo development. Here we map their chromatin accessibility landscapes and show that naive specific open chromatin are enriched with motifs for Oct/Sox/Klf/TCF and primed one with AP1 motifs. The AP1 founding member c-Jun is expressed in EpiSCs and occupies both open and closed chromatin. Yet, c-Jun deficiency has no impact on the self renewal nor the transcription program of EpiSCs. However, in a Klf4-driven reprogramming system, we show that c-Jun-/- EpiSCs undergo primed to naive transition more efficiently than wild type cells and Klf4 evicts c-JUN from wild type chromatin. These results suggest that c-Jun is a pioneer factor not to regulate transcription but to prevent backward reprogramming during naive-primed transition, thus providing a molecular basis for the forward principle in development.

2020-12-31 | GSE127925 | GEO

c-JUN is a pioneer factor safeguarding the primed state of pluripotency (ChIP-Seq)

Project description:Mouse ESCs and EpiSCs represent naive and primed states of plurioptency corresponding to two consecutive stages of embryo development. Here we map their chromatin accessibility landscapes and show that naive specific open chromatin are enriched with motifs for Oct/Sox/Klf/TCF and primed one with AP1 motifs. The AP1 founding member c-Jun is expressed in EpiSCs and occupies both open and closed chromatin. Yet, c-Jun deficiency has no impact on the self renewal nor the transcription program of EpiSCs. However, in a Klf4-driven reprogramming system, we show that c- Jun-/- EpiSCs undergo primed to naive transition more efficiently than wild type cells and Klf4 evicts c-JUN from wild type chromatin. These results suggest that c-Jun is a pioneer factor not to regulate transcription but to prevent backward reprogramming during naive-primed transition, thus providing a molecular basis for the forward principle in development.

2020-12-31 | GSE127921 | GEO

c-JUN is a pioneer factor safeguarding the primed state of pluripotency (ATAC-Seq)

Project description:Mouse ESCs and EpiSCs represent naive and primed states of plurioptency corresponding to two consecutive stages of embryo development. Here we map their chromatin accessibility landscapes and show that naive specific open chromatin are enriched with motifs for Oct/Sox/Klf/TCF and primed one with AP1 motifs. The AP1 founding member c-Jun is expressed in EpiSCs and occupies both open and closed chromatin. Yet, c-Jun deficiency has no impact on the self renewal nor the transcription program of EpiSCs. However, in a Klf4-driven reprogramming system, we show that c- Jun-/- EpiSCs undergo primed to naive transition more efficiently than wild type cells and Klf4 evicts c-JUN from wild type chromatin. These results suggest that c-Jun is a pioneer factor not to regulate transcription but to prevent backward reprogramming during naive-primed transition, thus providing a molecular basis for the forward principle in development.

2020-12-31 | GSE127920 | GEO

TFAP2C regulates transcription in human naive pluripotency by opening enhancers

Project description:Naive and primed pluripotent human embryonic stem cells bear transcriptional similarity to pre- and post-implantation epiblast and thus constitute a developmental model for understanding the pluripotent stages in human embryo development. To identify new transcription factors that differentially regulate the unique pluripotent stages, we mapped open chromatin using ATAC-seq and found enrichment of the activator protein-2 (AP2) transcription factor binding motif at naive-specific open chromatin. We determined that the AP2 family member TFAP2C is upregulated during primed to naive reversion and becomes widespread at naive-specific enhancers. TFAP2C functions to maintain pluripotency and repress neuroectodermal differentiation during the transition from primed to naive by facilitating the opening of enhancers proximal to pluripotency factors. Additionally, we identify a previously undiscovered naive-specific POU5F1 (OCT4) enhancer enriched for TFAP2C binding. Taken together, TFAP2C establishes and maintains naive human pluripotency and regulates OCT4 expression by mechanisms that are distinct from mouse.

2018-04-25 | GSE101074 | GEO

Single Cell Sequencing Reveals Early PGC-like Intermediates During Mouse Primed to Naïve Transition

Project description:Single cell analysis provides clarity unattainable with bulk approaches. Here we apply single cell RNA-seq to a newly established BMP4 induced mouse primed to naive transition (Bi-PNT) system and show that the reset is not a direct reversal of cell fate but through developmental intermediates. We first show that mEpiSCs bifurcate into c-Kit+ naïve and c-Kit- placenta-like cells, among which, the naive branch undergoes further transition through a primordial germ cell-like cells (PGCLCs) intermediate capable of spermatogenesis in vivo. Indeed, deficiency of Prdm1/Blimp1, the key regulator for PGC specification, blocks the induction of PGCLCs and naïve cells. Instead, Gata2 knockout arrests placenta-like fate, but facilitates the generation of PGCLCs. Our results not only reveal a newly cell fate dynamics between primed and naive states at single-cell resolution, but also provide a model system to explore mechanisms involved in regaining germline competence from primed pluripotency.

2021-03-09 | GSE147088 | GEO

Zfp281 Coordinates Opposite Functions of Tet1 and Tet2 for Alternative Pluripotent States [RNA-Seq]

Project description:Pluripotent cell identity comprises a spectrum of cell states including naive and primed states, which are typified by mouse embryonic stem cells (ESCs) and epiblast-derived stem cells (EpiSCs), respectively. Here we define a pluripotent cell fate (PCF) gene signature based on RNA-seq analysis associated with naive and primed pluripotency acquisition, and identify Zfp281 as a key transcriptional regulator for primed pluripotency and also as a barrier to achieve the naive pluripotency of both mouse and human ESCs.

2016-06-28 | GSE81044 | GEO

Zfp281 Coordinates Opposite Functions of Tet1 and Tet2 for Alternative Pluripotent States [ChIP-Seq]

2016-06-28 | GSE81042 | GEO

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