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EED-mediated histone methylation is critical for CNS myelination and remyelination by inhibiting WNT, BMP, and senescence pathways.

ABSTRACT: Mutations in the polycomb repressive complex 2 (PRC2) can cause Weaver-like syndrome, wherein a patient cohort exhibits abnormal white matter; however, PRC2 functions in CNS myelination and regeneration remain elusive. We show here that H3K27me3, the PRC2 catalytic product, increases during oligodendrocyte maturation. Depletion of embryonic ectoderm development (EED), a core PRC2 subunit, reduces differentiation of oligodendrocyte progenitors (OPCs), and causes an OPC-to-astrocyte fate switch in a region-specific manner. Although dispensable for myelin maintenance, EED is critical for oligodendrocyte remyelination. Genomic occupancy and transcriptomic analyses indicate that EED establishes a chromatin landscape that selectively represses inhibitory WNT and bone morphogenetic protein (BMP) signaling, and senescence-associated programs. Blocking WNT or BMP pathways partially restores differentiation defects in EED-deficient OPCs. Thus, our findings reveal that EED/PRC2 is a crucial epigenetic programmer of CNS myelination and repair, while demonstrating a spatiotemporal-specific role of PRC2-mediated chromatin silencing in shaping oligodendrocyte identity and lineage plasticity.

SUBMITTER: Wang J

PROVIDER: S-EPMC7423366 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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EED-mediated histone methylation is critical for CNS myelination and remyelination by inhibiting WNT, BMP, and senescence pathways.

Wang Jiajia J Yang Lijun L Dong Chen C Wang Jincheng J Xu Lingli L Qiu Yueping Y Weng Qinjie Q Zhao Chuntao C Xin Mei M Lu Q Richard QR

Science advances 20200812 33

Mutations in the polycomb repressive complex 2 (PRC2) can cause Weaver-like syndrome, wherein a patient cohort exhibits abnormal white matter; however, PRC2 functions in CNS myelination and regeneration remain elusive. We show here that H3K27me3, the PRC2 catalytic product, increases during oligodendrocyte maturation. Depletion of embryonic ectoderm development (EED), a core PRC2 subunit, reduces differentiation of oligodendrocyte progenitors (OPCs), and causes an OPC-to-astrocyte fate switch in ...[more]

PMID: 32851157

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Dataset Information

EED-mediated histone methylation is critical for CNS myelination and remyelination by inhibiting WNT, BMP, and senescence pathways.

Publications

EED-mediated histone methylation is critical for CNS myelination and remyelination by inhibiting WNT, BMP, and senescence pathways.

Similar Datasets

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