Understanding the regulation and the function of a central regulatory circuit orchestrating meiotic gene expression during mammalian spermatogenesis

Sperm development—central to male reproductive health—comprises an intricate and exquisitely programmed process of stem cell self-renewal, meiosis, and differentiation.

The orderly progression of meiosis and subsequent differentiation of sperm depends on a dynamic and highly regulated gene expression program. The mechanisms that control meiotic gene expression remain poorly defined.

Preliminary studies have revealed that the testis-specific transcription factors A-MYB and TCFL5 comprise a feed-forward regulatory loop that controls meiotic gene expression, including the transcription of meiotic transcripts that are processed into pachytene piRNAs—small silencing RNAs that bind PIWI proteins—whose exact functions remain mysterious.

The first goal of this proposal is to decipher how the regulatory circuit is controlled and how it regulates the meiotic gene expression program.

Genetic, biochemical and proteomic approaches will be used to study how post-translational modifications regulate TCFL5 function and to identify additional components of the circuit.

My recent study reveals that pachytene piRNA genes are rapidly diverging, suggesting that the evolution of piRNA genes favors sequence diversity. The second goal of this proposal is to use molecular approaches to shed light on the evolutionary function of piRNAs.

These studies will advance our understanding of sperm development, reveal mechanisms of infertility, and suggest approaches to promote fertility.