PCGF1/PRC1.1 selectively sustains astroglial lineage progression by repressing N4bp1 to stabilize Notch signaling

Abstract

Abstract The generation of distinct neural lineages from common progenitors requires coordinated regulation by developmental signaling pathways and epigenetic mechanisms. Although extracellular signals such as Notch promote astrocyte differentiation, how epigenetic mechanisms establish the competence of progenitors to respond to these cues remains poorly understood. Here, we identify PCGF1 (NSPC1), a core component of the non-canonical Polycomb repressive complex PRC1.1, as an epigenetic regulator of cortical astroglial lineage progression. Conditional deletion of Pcgf1 in the dorsal forebrain selectively impairs astrocyte generation without affecting neurogenesis, cortical lamination, or the abundance of EGFR-positive gliogenic progenitors. Pcgf1 deficiency impairs the progression toward astroglial-associated states and reduces SOX9 + , BLBP + , GFAP + , and ALDH1L1+ populations. Mechanistically, PCGF1 directly represses N4bp1, a negative regulator of the Notch intracellular domain (NICD). Loss of Pcgf1 leads to N4BP1 upregulation, NICD destabilization, and attenuation of Notch signaling, whereas N4bp1 deletion produces the opposite astroglial phenotype. Our findings reveal a PRC1.1-dependent mechanism that promotes astroglial lineage progression by sustaining developmental signaling output, establishing the PCGF1–N4BP1–Notch axis as a molecular link between chromatin regulation and neural lineage diversification.

The authors' abstract, as published at the source. EMBO Reports, 2026 · DOI ↗