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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE146653 | GEO | 2020/06/16

REPOSITORIES: GEO

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BMP4 Resets Primed to Naive Pluripotency by Reprogramming Chromatin Accessibility [RNA-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 | GSE122936 | GEO

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

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.

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BMP4 Resets Primed to Naive Pluripotency by Reprogramming Chromatin Accessibility

Project description:BMP4 Resets Primed to Naive Pluripotency by Reprogramming Chromatin Accessibility

| PRJNA506966 | ENA

Defining Essential Regulators of Naïve Human Pluripotent Cell Reprogramming

Project description:Defining how human pluripotent cell identity is controlled and in particular how naïve pluripotency is acquired during cell reprogramming is crucial for the future applications of pluripotent stem cells. However, the regulatory pathways of naïve cell reprogramming remain incompletely understood. Here, we used genome-wide CRISPR-Cas9 screening to identify novel regulators of primed to naïve pluripotent stem cell reprogramming, including genes that are essential for reprogramming and genes that normally impede reprogramming and whose targeted deletion led to enhanced reprogramming. Integrated analysis defined specific chromatin complexes and signalling pathways as critical regulators of naïve reprogramming, and were largely distinct from regulators of somatic cell reprogramming. Mechanistically, PRC1.3 and PRDM14 are jointly required to transcriptionally repress developmental and gene regulatory factors to ensure naïve cell reprogramming. Additionally, small molecule inhibitors of reprogramming impediments increased the efficiency of naïve cell reprogramming, and are of practical benefit that can improve on current reprogramming methods. Taken together, we have identified novel regulators controlling the establishment of naïve pluripotency in human cells, which will open up new ways to exploit the full potential of pluripotent stem cells. These results also provide new insights into mechanisms that destabilise and reconfigure cell identity during cell state transitions.

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2021-03-09 | GSE147088 | GEO

RNA-seq with knockdown ZBTB7A and NTC control

Project description:Zinc finger and BTB domain containing transcription repressor ZBTB7A has been recently reported as a tumor suppressor who plays important functions to prevent the progression of prostate cancer. However, the chromatin activity of ZBTB7A in prostate cancer cells remain unclear. In order to identify the cistrome and transcriptome of ZBTB7A, we performed ZBTB7A ChIP-seq in VCaP cells and RNA-seq in VCaP cells transfected with siRNA targeting ZBTB7A or non-targeting control, respectively (cells were grown in full serum). By using combined ChIP-seq and RNA-seq analyses in VCaP cells, we have precisely mapped the ZBTB7A binding sites and identified a subset of genes that are directly repressed by ZBTB7A. To study the chromatin interaction of ZBTB7A with androgen receptor (AR), we also performed ChIP-seq of ZBTB7A in VCaP cells stimulated with 10 nM DHT for 4 hours versus vehicle control (cells were hormone-depleted prior to DHT stimulation). Our results show that ZBTB7A binding is increased by androgen at AR and ZBTB7A overlapping sites.

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ZBTB7A ChIP-seq under different DHT level

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