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

Abstract

SUMMARY 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.

Single-cell CUT&Tag profiles histone modifications and transcription factors in complex tissues

“…This is most prominent for H3K27me3, which is enriched in populations of oligodendrocytes, microglia and a subset of neurons, relative to the other populations ( Figure 3d ). Enrichment of H3K27me3 in oligodendrocytes is consistent with the recent finding that H3K27me3 drives oligodendrocyte-astrocyte switch during development 28 . Interestingly, we also observed relatively higher amounts of H3K36me3 in the population of immature oligodendrocytes (OPC/COP-NFOL stages) ( Figure 3d ).…”

PRC1 sustains the integrity of neural fate in the absence of PRC2 function

“…Consistent with this idea, recent studies on the effects of PRC2 depletion in intestinal stem cells indicate that ~40% of residual H3K27me3 can maintain PRC repression (Jadhav et al, 2020), although the extent of derepression varies with gene target. Although we observed no MN phenotypes in Ezh or Eed mutants, later-born oligodendrocytes derived from the MN progenitor domain have been shown to depend on PRC2 function for their differentiation (Wang et al, 2020). This more pronounced effect on glial development likely reflects further dilution of H3K27me3 through cell division in PRC2 mutants.…”

PRC1 Sustains the Memory of Neuronal Fate Independent of PRC2 Function

“…During neural differentiation, the rate of cell division decreases (Kicheva et al, 2014;Wilcock et al, 2007), potentially limiting H3K27me3 reduction, and enabling PRC1 to bind at target loci, even in the absence of de novo H3K27 methylation. Although we observed no MN phenotypes in Ezh or Eed mutants, later-born oligodendrocytes that derive from the same precursors as MNs have been shown to depend on PRC2 function for their differentiation (Wang et al, 2020). This more pronounced effect on glial development likely reflects further dilution of H3K27me3 through cell division in PRC2 mutants.…”