ALKBH5 is required to maintain proper SETDB1 protein levels associated with meiotic sex chromosome inactivation.
TL;DR
It is reported that Alkbh5-knockout spermatocytes exhibit normal double-strand break (DSB) formation, homologous recombination and synapsis on autosomes but impaired synapsis between sex chromosomes.
Abstract
N6-methyladenosine (m6A) is the most abundant RNA modification in eukaryotes. ALKBH5 is an m6A demethylase that is essential for spermatogenesis. However, its function in meiotic prophase remains elusive. Here, we report that Alkbh5-knockout spermatocytes exhibit normal double-strand break (DSB) formation, homologous recombination and synapsis on autosomes but impaired synapsis between sex chromosomes. ALKBH5 depletion causes a significantly upregulated transcriptome on sex chromosomes and meiotic sex chromosome inactivation (MSCI) defects in spermatocytes at the pachytene stage. Mechanistically, ALKBH5 regulates SETDB1 expression in a post-transcriptional manner. Alkbh5 knockout inhibits SETDB1 protein expression, leading to the decreased SETDB1 signals on sex chromosomes and subsequently inhibiting H3K9me3 to form heterochromatin and silence transcriptional activity. Taken together, our findings identify ALKBH5 as a critical regulator of male meiosis by demonstrating that it is required to maintain proper SETDB1 protein levels, which in turn ensures the faithful execution of MSCI.