ATAC-seq of Cerebellar granule cell precursors of control and Sin3A CKO mice.

Cerebellar granule cells (GCs) are critical for motor and cognitive functions. Lineage tracing studies have identified a hierarchical developmental progression of GC neurogenesis, transitioning from Sox2+ stem-like quiescent cells to Atoh1+ rapidly proliferating granule cell precursors (GCPs), and ultimately to NeuN+ mature GCs. However, the molecular mechanisms governing these transitions remain poorly understood. Here, we demonstrate that Sin3A, a core component of the histone deacetylase (Hdac) complex, plays a sequentially essential role in driving GC lineage progression across distinct precursor stages. In Sox2+ cells, Sin3A facilitates their transition to GCPs by repressing Sox2 expression. In GCPs, Sin3A suppresses Atoh1 transcriptional activity by recruiting Neurod1 as a co-repressor, thereby promoting GCP differentiation. Additionally, Sin3A ensures the survival and specification of GCPs by repressing non-lineage-specific gene expression. Our findings highlight the central role of the Sin3A complex in orchestrating distinct stages of cerebellar GC lineage development.