Mus musculus Transcriptome

Rapamycin is a clinically important drug used in transplantation and cancer therapy, but causes a number of side effects, including male infertility. Its canonical target, mTOR complex 1 (mTORC1)plays key roles in metabolism and binds chromatin, however its precise role in the male germ line has not been elucidated. Here we inactivate the core component Raptor to show that mTORC1 function is critical for male meiosis and inactivation of sex chromosomes. Disruption of the Raptor gene impaired synapsis in both sex chromosomes and autosomes and prevented the efficient spreading of silencing factors into the XY chromatin. Accordingly, mRNAs for XY-linked genes remained inappropriately expressed in Raptor deficient mice. Molecularly, the failure to suppress gene expressing corresponded to deficiencies in two repressive chromatin markers, H3K9 dimethylation and H3K9 trimethylation in the XY body. Together, these results demonstrate that mTORC1 has an essential role in meiotic processing and silencing of sex chromosomes in the male germ line, which may explain the infertility associated with inhibitors such as rapamycin.