Kärt Mätlik1, Eve-Ellen Govek1, Matthew R. Paul2, C. David Allis3 and Mary E. Hatten1 1Laboratory of Developmental Neurobiology, Rockefeller University, New York, New York 10065, USA; 2Bioinformatics Resource Center, Rockefeller University, New York, New York 10065, USA; 3Laboratory of Chromatin Biology and Epigenetics, Rockefeller University, New York, New York 10065, USA Corresponding author: hattenrockefeller.edu Abstract

Developing neurons undergo a progression of morphological and gene expression changes as they transition from neuronal progenitors to mature neurons. Here we used RNA-seq and H3K4me3 and H3K27me3 ChIP-seq to analyze how chromatin modifications control gene expression in a specific type of CNS neuron: the mouse cerebellar granule cell (GC). We found that in proliferating GC progenitors (GCPs), H3K4me3/H3K27me3 bivalency is common at neuronal genes and undergoes dynamic changes that correlate with gene expression during migration and circuit formation. Expressing a fluorescent sensor for bivalent domains revealed subnuclear bivalent foci in proliferating GCPs. Inhibiting H3K27 methyltransferases EZH1 and EZH2 in vitro and in organotypic cerebellar slices dramatically altered the expression of bivalent genes, induced the down-regulation of migration-related genes and up-regulation of synaptic genes, inhibited glial-guided migration, and accelerated terminal differentiation. Thus, histone bivalency is required to regulate the timing of the progression from progenitor cells to mature neurons.

Received March 2, 2023. Accepted July 10, 2023.