Genomic Research Sheds Light on Possible Causes of Male Infertility
Research at Cincinnati Children’s has identified a critical determinant of the germline epigenome that has important implications for the genomics and evolution of the male germline.
The study, published online February, 19, 2015 in the journal Developmental Cell, advances research into the possible causes of male infertility, says senior author Satoshi Namekawa, PhD.
Namekawa and colleagues found that genes commonly expressed in somatic lineages and spermatogenesis-progenitor cells undergo a repression in a genome-wide manner. This repression occurs in the late developmental stages of the male germline, the only lineage that ensures the perpetuation of genetic and epigenetic information across generations.
The research team theorizes that this repression may, in turn, indirectly ensure activation of spermatogenesis-specific genes, an essential step for producing mature spermatozoa. Disruptions to this normal process may explain some forms of male infertility because this mechanism underlies activation of essential genes in spermatogenesis.
The study identifies SCML2, a germline-specific subunit of a polycomb repressive complex 1 (PRC1), as the critical determinant of the germline epigenome. SCML2 establishes the unique epigenome of the germline through two distinct and antithetical mechanisms:
- SCML2 works with PRC1 to promote ubiquitination of histone H2A, a histone modification associated with gene repression, in the stem cell phase of spermatogenesis-progenitor cells. This process appears to mark somatic/progenitor genes on autosomes for repression.
- At the same time, SCML2 also prevents ubiquitination of histone H2A on sex chromosomes during meiosis, thereby enabling unique epigenetic programming of sex chromosomes for male reproduction.
The key finding was revealing essential mechanisms underlying spermatogenesis, which will lead to more focused exploration of how the mechanisms of reproduction operate.
“It is tempting,” Namekawa says, “to speculate that these mechanism may underlie cancer because the germline program is usually suppressed in normal somatic cells, but is ectopically activated in various cancer cells. SCML2 may be one of so called, cancer testis genes. Our study might have revealed an evolutionarily conserved mechanism underlying complexity of the germline and cancer programs.”
