PRC2 Acts as a Critical Timer That Drives Oligodendrocyte Fate over Astrocyte Identity by Repressing the Notch Pathway

• Published in: Cell reports (Cambridge) Vol. 32; no. 11; p. 108147
• Main Authors: Wang, Wenxian, Cho, Hyeyoung, Kim, Dongkyeong, Park, Younjung, Moon, Ji Hwan, Lim, Su Jeong, Yoon, Sung Min, McCane, Michael, Aicher, Sue A., Kim, Sangsoo, Emery, Ben, Lee, Jae W., Lee, Seunghee, Park, Yungki, Lee, Soo-Kyung
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.09.2020
• Subjects: Animals; astrocyte; Astrocytes - cytology; Astrocytes - metabolism; Cell Differentiation; Cell Lineage; Chickens; EED; Enhancer of Zeste Homolog 2 Protein - metabolism; Ezh2; H3K27me3; Histones - metabolism; Lysine - metabolism; Methylation; Mice; Myelin Sheath - metabolism; myelination; NFI Transcription Factors - metabolism; NFIA; Notch pathway; oligodendrocyte; Oligodendroglia - cytology; Oligodendroglia - metabolism; Polycomb Repressive Complex 2 - metabolism; PRC2; Receptors, Notch - metabolism; Signal Transduction; Spinal Cord - cytology; Spinal Cord - ultrastructure; Stem Cells - cytology; Stem Cells - metabolism; Wnt pathway; Wnt Signaling Pathway; Notch pathway; PRC2; NFIA; EED; Wnt pathway; oligodendrocyte; myelination; astrocyte; Ezh2; H3K27me3
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2020.108147

PRC2 creates the repressive mark histone H3 Lys27 trimethylation. Although PRC2 is involved in various biological processes, its role in glial development remains ambiguous. Here, we show that PRC2 is required for oligodendrocyte (OL) differentiation and myelination, but not for OL precursor formation. PRC2-deficient OL lineage cells differentiate into OL precursors, but they fail to trigger the molecular program for myelination, highlighting that PRC2 is essential for directing the differentiation timing of OL precursors. PRC2 null OL lineage cells aberrantly induce Notch pathway genes and acquire astrocytic features. The repression of the Notch pathway restores the myelination program and inhibits abnormal astrocytic differentiation in the PRC2-deficient OL lineage, indicating that Notch is a major target of PRC2. Altogether, our studies propose a specific action of PRC2 as a novel gatekeeper that determines the glial fate choice and the timing of OL lineage progression and myelination by impinging on the Notch pathway. [Display omitted] •PRC2 null oligodendrocyte (OL) lineage cells fail to differentiate to OL•PRC2 null OL lineage cells aberrantly upregulate Notch and Wnt pathway genes•The inhibition of Notch and Wnt restores OL differentiation in PRC2 null OL cells•The Notch inhibition blocks aberrant astrocytic gene induction in PRC2 null OL cells Wang et al. show that the polycomb repressive complex PRC2 is required for the differentiation of oligodendrocyte precursors to myelinating oligodendrocytes. They further show that PRC2 promotes oligodendrocyte differentiation and inhibits erroneous astrocytic fate by repressing the Notch pathway.