SCML2 Establishes the Male Germline Epigenome through Regulation of Histone H2A Ubiquitination

Abstract

SUMMARY Gametogenesis is dependent on the expression of germline-specific genes. However, it remains unknown how the germline epigenome is distinctly established from that of somatic lineages. Here we show that genes commonly expressed in somatic lineages and spermatogenesis-progenitor cells undergo repression in a genome-wide manner in late stages of the male germline and identify underlying mechanisms. SCML2, a germline-specific subunit of a Polycomb repressive complex 1 (PRC1), establishes the unique epigenome of the male germline through two distinct antithetical mechanisms. SCML2 works with PRC1 and promotes RNF2-dependent ubiquitination of H2A, thereby marking somatic/progenitor genes on autosomes for repression. Paradoxically, SCML2 also prevents RNF2-dependent ubiquitination of H2A on sex chromosomes during meiosis, thereby enabling unique epigenetic programming of sex chromosomes for male reproduction. Our results reveal divergent mechanisms involving a shared regulator by which the male germline epigenome is distinguished from that of the soma and progenitor cells.

Functional significance of the sex chromosomes during spermatogenesis

“…Another proteomics study independently identified SCML2 as a meiosis-specific protein (Luo, et al 2013). Scml2 is highly transcribed in spermatogonia, but then subject to MSCI in spermatocytes due to its X-linkage (Hasegawa, et al 2015), consistent with a previous report using RNA FISH (fluorescence in situ hybridization) analysis (Mueller, et al 2008). SCML2 protein is detected in the entire nuclei of undifferentiated spermatogonia and persists until meiosis, where it becomes accumulated on the XY body despite its transcriptional silencing (Hasegawa, et al 2015, Luo, et al 2015).…”

“…Scml2 is highly transcribed in spermatogonia, but then subject to MSCI in spermatocytes due to its X-linkage (Hasegawa, et al 2015), consistent with a previous report using RNA FISH (fluorescence in situ hybridization) analysis (Mueller, et al 2008). SCML2 protein is detected in the entire nuclei of undifferentiated spermatogonia and persists until meiosis, where it becomes accumulated on the XY body despite its transcriptional silencing (Hasegawa, et al 2015, Luo, et al 2015). Scml2 knockout mice are infertile (Hasegawa, et al 2015), while an independent Scml2 knockout mouse line with a distinct genetic background exhibits severely compromised fertility (Luo, et al 2015).…”

“…SCML2, a germline-specific Polycomb protein, was identified as a component of γH2AX (histone variant H2AX phosphorylated at serine 139, an essential histone modification of the XY body)-containing nucleosomes from testes (Hasegawa, et al 2015). Another proteomics study independently identified SCML2 as a meiosis-specific protein (Luo, et al 2013).…”

Sex comb on midleg like-2 is a novel specific marker for the diagnosis of gastroenteropancreatic neuroendocrine tumors

“…SCML2 is specifically expressed in germ cells of mice, and loss of SCML2 reduces sperm production. SCML2 also regulates the epigenetic state of sex chromosomes during male meiosis (24)(25)(26). Human SCML2 gene encodes two protein isoforms: SCML2A (chromatin-bound) and SCML2B (nucleoplasmic).…”

The histone codes for meiosis

“…Sex comb on midleglike 2 (SCML2) is a germline-specific subunit of PRC1, and it can promote RNF2-dependent ubiquitination of H2A to mark somatic/progenitor genes on autosomes for repression. SCML2 can also recruit USP7, a deubiquitinase, to the XY body in spermatocytes, thereby preventing RNF2-dependent ubiquitination of H2A on sex chromosomes during meiosis and enabling unique epigenetic programming of sex chromosomes for male reproduction (Nakagawa et al 2008, Hasegawa et al 2015, Luo et al 2015. UBR2, an N-end rule proteolytic pathway ubiquitin ligase, can also catalyze H2A ubiquitination by promoting the HR6B (E2)-H2A interaction and the HR6B-to-H2A transfer of ubiquitin.…”