Miz1 Controls Schwann Cell Proliferation via H3K36 me2 Demethylase Kdm8 to Prevent Peripheral Nerve Demyelination

Schwann cell differentiation and myelination depends on chromatin remodeling, histone acetylation, and methylation, which all affect Schwann cell proliferation. We previously reported that the deletion of the POZ (POxvirus and Zinc finger) domain of the transcription factor Miz1 (Myc-interacting zinc finger protein; encoded by ) in mouse Schwann cells ( Δ ) causes a neuropathy at 90 d after birth [postnatal day (P) 90], with a subsequent spontaneous regeneration. Here we show that RNA sequencing from Δ and control animals at P30 revealed a set of upregulated genes with a strong correlation to cell-cycle regulation. Consistently, a subset of Schwann cells did not exit the cell cycle as observed in control animals and the growth fraction increased over time. From the RNAseq gene list, two direct Miz1 target genes were identified, one of which encodes the histone H3K36 demethylase Kdm8. We show that the expression of is repressed by Miz1 and that its release in Δ cells induces a decrease of H3K36 , especially in deregulated cell-cycle-related genes. The linkage between elevated expression, hypomethylation of H3K36 at cell-cycle-relevant genes, and the subsequent re-entering of adult Schwann cells into the cell cycle suggests that the release of repression in the absence of a functional Miz1 is a central issue in the development of the Δ phenotype. The deletion of the Miz1 (Myc-interacting zinc finger protein 1) POZ (POxvirus and Zinc finger) domain in Schwann cells causes a neuropathy. Here we report sustained Schwann cell proliferation caused by an increased expression of the direct Miz1 target gene , encoding a H3K36me2 demethylase. Hence, the demethylation of H3K36 is linked to the pathogenesis of a neuropathy.