Abstract
Polycomb group proteins mediate transcriptional silencing in diverse developmental processes. Sex chromosomes undergo chromosome-wide transcription silencing during male meiosis. Here we report that mouse SCML2 (Sex comb on midleg-like 2), an X chromosome-encoded polycomb protein, is specifically expressed in germ cells, including spermatogonia, spermatocytes, and round spermatids. SCML2 associates with phosphorylated H2AX and localizes to the XY body in spermatocytes. Loss of SCML2 in mice causes defective spermatogenesis, resulting in sharply reduced sperm production. SCML2 interacts with and recruits a deubiquitinase, USP7, to the XY body in spermatocytes. In the absence of SCML2, USP7 fails to accumulate on the XY body, whereas H2A monoubiquitination is dramatically augmented in the XY chromatin. Our results demonstrate that the SCML2/USP7 complex constitutes a novel molecular pathway in modulating the epigenetic state of sex chromosomes during male meiosis.
Highlights
Polycomb group (PcG) proteins are key epigenetic factors in maintaining transcriptional silencing during development in higher eukaryotes [1]
Polycomb group proteins control the expression of homeotic genes in developmental patterning by catalyzing post-translational modifications of histones—core protein components of the chromatin
The SCML2 protein localizes to the XY chromatin in germ cells during male meiosis, which undergoes chromosome-wide transcriptional silencing
Summary
Polycomb group (PcG) proteins are key epigenetic factors in maintaining transcriptional silencing during development in higher eukaryotes [1]. PcG proteins form chromatin-modifying complexes, notably polycomb repressive complex 1 (PRC1) and PRC2. PRC2 mediates trimethylation of histone H3 on lysine 27 (H3K27me3) through its methyl transferase activity. PRC1 mediates monoubiquitination of histone H2A at lysine 119 through the ubiquitin E3 ligase activity of one of its components—RNF2 [3]. H2A ubiquitination is linked with transcriptional silencing and X-inactivation [3, 4]. Self-ubiquitination of RNF2 is required for its ubiquitin E3 ligase activity [5]. USP7, a deubiquitinating enzyme, directly deubiquitinates RNF2 [5]. These studies demonstrate the intricacy in the regulation of polycomb protein-mediated silencing
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