Postmitotic Dynamics in Chromatin Modification and Regulatory Topology Underlie Cerebellar Granule Maturation

Neurons are remarkably long-lived cells that are born early on in development and maintained over the lifespan of an organism. Their birth is followed by their iterative maturation into functional neurons that can participate in CNS circuitry. This involves the temporally regulated programs of gene transcription enabling them to migrate, generate axons, dendrites, synapses, and spatial connections with other cells within their niche. This is mediated at least in part by dynamics in chromatin biology, as mutations in chromatin regulators are strongly implicated in the advent of neurodevelopmental and neuropsychiatric disorders. The mechanisms by which chromatin dynamics orchestrate neuronal maturation remain poorly understood. We find that the postnatal maturation of cerebellar granule neurons (CGNs) requires dynamic changes in the genomic distribution of histone H3 lysine 27 trimethylation (H3K27me3), demonstrating a causal function for this chromatin modification in gene regulation beyond its canonical role in cell fate specification. The developmental loss of H3K27me3 at promoters of genes that turn on as CGNs mature is facilitated by the lysine demethylase, and ASD-risk gene, Kdm6b, through its catalytic activity. Interestingly, inhibition of the H3K27 methyltransferase EZH2 in newborn CGNs not only blocks the repression of progenitor genes but also impairs the induction of mature CGN genes, showing the importance of bidirectional H3K27me3 regulation across the genome. We also find dynamics in regulatory chromatin topology to facilitate the interaction between cerebellar enhancers and their cognate genes during cerebellar maturation, that appears to be poised by H3K27me3. These data demonstrate that dynamics at the level of chromatin primary, secondary, and tertiary structures in developing postmitotic neurons regulate the temporal coordination of gene expression programs that underlie functional neuronal maturation.