Many RNA regulatory processes are significantly more active in long-lived stem cells than in their differentiated counterparts. Central to this regulation are small RNAs and their associated proteins. We specifically investigate the piRNAs and their binding partners, the PIWI proteins. These factors are uniquely and consistently enriched in pluripotent stem cells across a wide evolutionary range, from cnidarians to urochordates. Crucially, depleting these factors typically leads to a complete loss of regenerative abilities, underscoring their essential role in maintaining stem cell function.

The S. mediterranea PIWI protein family consists of three members: two that are critical for short-term survival and a third with long-term phenotypic effects. Our lab uses molecular, cell biological, and genetic approaches to investigate how these proteins and their associated piRNAs support stem cell health. By analyzing their effects at both the RNA and chromatin level, we seek to uncover the mechanisms by which they regulate stem cell maintenance and the transition to differentiated tissues.

The piRNA pathway is best known as a genomic immune system that silences transposons, but how it accurately distinguishes transposon transcripts from mRNAs remains unclear. piRNAs are generated from specific genomic regions named piRNA clusters, that carry antisense sequences against mobile elements. Yet, because transposons are fast-evolving targets, the piRNA machinery must be highly adaptive. It thus faces a dual challenge: it must be specific enough to avoid harming cellular mRNAs, but flexible enough to recognize and neutralize new threats. We use computational and molecular methods to reveal how the piRNA system combines these two opposing traits: specificity and flexibility.

In further ongoing work, we also address the contributions of other non-coding RNA to stem cell function, including long non-coding RNA and siRNA.