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RBBP4 regulates pluripotent-to-2C-like state transition through modulating heterochromatin assembly (ChIP-Seq)

ABSTRACT: Cellular totipotency is critical for generating a whole organism, yet how to establish totipotency is still poorly illustrated. Unlike pluripotent stem cells, abundant transposable elements (TEs) are activated in the totipotent cells. Here, we show that histone chaperone RBBP4 but not its homologous RBBP7 is indispensable in maintaining the identity of mouse embryonic stem cells (mESCs). Auxin-induced degradation of RBBP4, but not RBBP7, reprograms pluripotent state to a totipotent-like (also known as 2C-like) state. Mechanistically, RBBP4 could recruit G9a and KAP1 to bind on retrotransposons, especially endogenous retroviruses. RBBP4 degradation reduces the binding of G9a-mediated H3K9me2 on ERVL (particularly MERVL) and KAP1-mediated H3K9me3 on ERV1/ERVK, respectively. Moreover, RBBP4 facilitates nucleosome occupancy through chromatin remodeler CHD4 and RBBP4 depletion leads to attenuation of CHD4 binding and nucleosome occupancy on TEs. Together, our study reveals the important roles of RBBP4 in heterochromatin assembly and its loss activates TEs in mESCs, opening a new way to obtain totipotent cells in vitro.

ORGANISM(S): Mus musculus

PROVIDER: GSE218652 | GEO | 2023/03/15

REPOSITORIES: GEO

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RBBP4 is an epigenetic barrier for inducing pluripotent stem cells to totipotent 2C-like cells [RNA-seq]

Project description:Cellular totipotency is critical for generating a whole organism, yet how to establish totipotency is still poorly illustrated. Unlike pluripotent stem cells, abundant transposable elements (TEs) are activated in the totipotent cells. Here, we show that histone chaperone RBBP4 but not its homologous RBBP7 is indispensable in maintaining the identity of mouse embryonic stem cells (mESCs). Auxin-induced degradation of RBBP4, but not RBBP7, reprograms pluripotent state to a totipotent-like (also known as 2C-like) state. Mechanistically, RBBP4 could recruit G9a and KAP1 to bind on retrotransposons, especially endogenous retroviruses. RBBP4 degradation reduces the binding of G9a-mediated H3K9me2 on ERVL (particularly MERVL) and KAP1-mediated H3K9me3 on ERV1/ERVK, respectively. Moreover, RBBP4 facilitates nucleosome occupancy through chromatin remodeler CHD4 and RBBP4 depletion leads to attenuation of CHD4 binding and nucleosome occupancy on TEs. Together, our study reveals the important roles of RBBP4 in heterochromatin assembly and its loss activates TEs in mESCs, opening a new way to obtain totipotent cells in vitro.

2023-03-15 | GSE221554 | GEO

RBBP4 is an epigenetic barrier for inducing pluripotent stem cells to totipotent 2C-like cells [scRNA-seq]

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RBBP4 regulates pluripotent-to-2C-like state transition through modulating heterochromatin assembly (Mnase-Seq)

2023-03-15 | GSE218655 | GEO

RBBP4 regulates pluripotent-to-2C-like state transition through modulating heterochromatin assembly (RNA-Seq)

2023-03-15 | GSE218651 | GEO

Individual retrotransposon integrants are differentially controlled by KZFP/KAP1-dependent histone methylation, DNA methylation and TET-mediated hydroxymethylation in naïve embryonic stem cells

Project description:The KZFP/KAP1 (KRAB zinc finger proteins/KRAB-associated protein 1) system plays a central role in the silencing of transposable elements (TEs) and the maintenance of parent-of-origin DNA methylation at imprinting control regions (ICRs) during the wave of genome-wide reprogramming that precedes implantation. In naïve murine embryonic stem cells (mESCs), the genome is maintained highly hypomethylated by a combination of active demethylation (operated by TET proteins) and lack of de novo methylation; in these cells, KAP1 is tethered by sequence-specific KZFPs to ICRs and TEs where it recruits histone and DNA methyltransferases to impose heterochromatin formation and DNA methylation. Here, upon removing either KAP1 or the cognate KZFP, we observed rapid TET-dependent accumulation of 5hmC at both ICRs and TEs. In absence of the KZFP/KAP1 complex, ICRs lost heterochromatic histone marks and underwent both active and passive DNA demethylation. Using RNA-seq, we further compared the expression profiles of TEs upon Kap1 removal in wild type, Dnmt and Tet triple knockout mESCs. We found that KAP1 represents the main effector of TEs repression in all three settings, yet we could additionally identify specific groups of TEs also controlled by DNA methylation. Furthermore, activation upon Kap1 removal in the absence of TET proteins could be either blunted or increased depending on TE subsets, indicating a complex interplay between heterochomatin and active demethylation in regulating the expression of the endovirome.

2018-02-28 | GSE95720 | GEO

Unbiased in vivo exploration of nuclear bodies-enhanced sumoylation reveals that PML orchestrates embryonic stem cell fate

Project description:Membrane-less organelles are condensates formed by phase separation whose functions often remain enigmatic. Upon oxidative stress, PML scaffolds Nuclear Bodies (NBs) to regulate senescence or metabolic adaptation, but their role in pluripotency remains elusive. Here we establish that PML is required for basal SUMO2/3 conjugation in mESCs and oxidative stress-driven sumoylation in mESCs or in vivo. PML NBs create an oxidationprotective environment for UBC9-driven SUMO2/3 conjugation of PML partners, often followed by their poly-ubiquitination and degradation. Differential in vivo proteomics identified several members of the KAP1 complex as PML NB-dependent SUMO2-targets. The latter drives functional activation of this key epigenetic repressor. Accordingly, Pml-/- mESCs reexpress transposable elements and display features of totipotent-like cells, a process further enforced by PML-controlled SUMO2-conjugation of DPPA2. Finally, PML is required for adaptive stress responses in mESCs. Collectively, PML orchestrates mESC fate through SUMO2-conjugation of key transcriptional or epigenetic regulators, raising new mechanistic hypotheses about PML roles in normal or cancer stem cells.

2022-09-14 | PXD028865 | Pride

Unbiased in vivo exploration of nuclear bodies-enhanced sumoylation reveals that PML orchestrates embryonic stem cell fate (II)

2023-03-06 | PXD032240 | Pride

Transposable elements and their KRAB-ZFP controllers regulate gene expression in adult tissues

Project description:The tetrapod-restricted KRAB-containing zinc finger proteins (KRAB-ZFPs) are essential early embryonic controllers of transposable elements (TEs), which they repress via their cofactor KAP1 and associated effectors through histone and DNA methylation, a process thought to result in irreversible silencing. Using a target-centered functional screen, we matched several murine TEs with their cognate KRAB-ZFP. This revealed an unexpected level of granularity in their interactions, with KRAB-ZFPs recognizing TEs from more than one subfamily, TEs recruiting more than one KRAB-ZFP, and spatially and temporally differential KRAB-ZFP-mediated regulation of TEs and nearby genes. Most importantly, we discovered that the KRAB/KAP1 system controls TEs in adult tissues, in cell culture and in vivo, where they partner up to regulate the expression of cellular genes. Therefore, TEs and KRAB-ZFPs establish widely active transcription networks that regulate not only development but probably also many physiological events. Given the high degree of species-specificity of both TEs and KRAB-ZFPs, these results have important implications for studying and understanding the biology of higher vertebrates, including humans. Analysis of transcriptional profiles of KAP1 or ZFP932/Gm15446 KO cells or tissues, and ZFP932 and Gm15446 ChIPseq in murine ES and C2C12 cells.

2016-03-15 | E-GEOD-74278 | biostudies-arrayexpress

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