Ybx1 negatively regulates PRC2 to affect gene expression programs for neural lineage specification and neural progenitor self-renewal and differentiation [RNA-seq]

Chromatin modifiers affect the spatiotemporal expression of gene expression programs that underlie organismal development. The Polycomb repressive complex 2 (PRC2) has emerged as a crucial player in executing neurodevelopmental programs. Here we show that the nucleic acid–binding protein Ybx1 interacts with PRC2 in human and mouse neural progenitor cells (NPCs). During early neural development in vivo, Ybx1 is required for forebrain specification and modulates mid/hindbrain growth. In NPCs, Ybx1 controls the self-renewal and neuronal differentiation. Mechanistically, Ybx1 binds PRC2 gene targets, reduces the levels of PRC2-mediated H3K27me3, and promotes the expression of genes in forebrain specification, cell proliferation, or neuronal differentiation. In Ybx1-knockout NPCs, H3K27me3 reduction by PRC2 enzymatic inhibitor or genetic depletion partially rescues the control of gene expression, self-renewal, and neuronal differentiation. Our findings suggest that Ybx1 modulates H3K27me3 by PRC2 to regulate spatiotemporal gene expression in embryonic neural development and uncover a crucial epigenetic mechanism balancing forebrain–hindbrain lineages and selfrenewal-differentiation choices in NPCs. Examination of YBX1, Ezh2, H3K4me3, H3K27me3 in WT and YBX1 KO mouse neural progenitor. Intergrated analysis with transcriptome.