Miz1 Controls Schwann Cell Proliferation via H3K36me2 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 Zbtb17) in mouse Schwann cells (Miz1ΔPOZ) causes a neuropathy at 90 d after birth [postnatal day (P) 90], with a subsequent spontaneous regeneration. Here we show that RNA sequencing from Miz1ΔPOZ 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 H3K36me2 demethylase Kdm8. We show that the expression of Kdm8 is repressed by Miz1 and that its release in Miz1ΔPOZ cells induces a decrease of H3K36me2, especially in deregulated cell-cycle-related genes. The linkage between elevated Kdm8 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 Kdm8 repression in the absence of a functional Miz1 is a central issue in the development of the Miz1ΔPOZ phenotype.SIGNIFICANCE STATEMENT 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 Kdm8, encoding a H3K36me2 demethylase. Hence, the demethylation of H3K36 is linked to the pathogenesis of a neuropathy.