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RBBP4 regulates pluripotent-to-2C-like state transition through modulating heterochromatin assembly (CUT&RUN)

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: GSE218653 | GEO | 2023/03/15

REPOSITORIES: GEO

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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.

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