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5-hydroxymethylcytosine is required for terminal differentiation of Purkinje neurons

ABSTRACT: Principal neurons in the mammalian brain exit cell cycle and execute a complex and prolonged differentiation program that continues into early adult life. Although high levels of 5-hydroxymethylcytosine (5hmC) accumulate in neurons, it is not known whether 5hmC can serve as an intermediate in DNA demethylation in postmitotic neurons. Here we report high resolution mapping of DNA methylation and hydroxymethylation, chromatin accessibility, and activating and repressive histone marks in developing postmitotic Purkinje cells (PCs). Our data reveal new relationships between PC transcriptional and epigenetic programs, and identify a class of late expressed genes that lose both 5mC and 5hmC during terminal differentiation. Deletion of the 5hmC writers Tet1, Tet2, and Tet3 from postmitotic Purkinje cells prevents loss of 5mC and 5hmC in regulatory domains and gene bodies and hinders transcriptional and epigenetic developmental transitions, resulting in hyper-excitability and increased susceptibility to excitotoxic drugs. Our data demonstrate that Tet-mediated active DNA demethylation occurs in vivo, and that acquisition of the precise molecular and electrophysiological properties of adult PCs requires continued oxidation of 5mC to 5hmC during the final phases of differentiation.

ORGANISM(S): Mus musculus

PROVIDER: GSE166423 | GEO | 2021/09/01

REPOSITORIES: GEO

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