Nelson C. Lau
Gene and Genome Regulation by RNAi Factors and Small RNAs
Small regulatory RNAs (and their associated proteins) are dynamic and active participants in controlling the genome and phenotype of cells and animals. Germ cells have a special role in the perpetuation of organisms, but they have also become the richest environment for the study of small regulatory RNAs. In addition to microRNAs, which are vital gene regulators conserved from plants to people, germ cells express endogenous small interfering RNAs (endo-siRNAs) and Piwi-interacting RNAs (piRNAs). In animal germ cells, such as spermatocytes and oocytes, piRNAs are the most abundant class of small RNAs, and together with Piwi proteins, they suppress the mobilization of transposable elements and specify the organization of mRNAs and proteins in the germ cell, which impacts the expression of certain genes.
Our group is interested in dissecting the molecular mechanisms of Piwi proteins and piRNAs, with a focus on particular outstanding questions. How exactly do Piwi proteins and piRNAs silence transposons and organize asymmetrically in germ cells? What is the impact of these molecules on global gene expression and chromatin organization and how does this affect germ cell and embryonic development? How does a cell explicitly generate piRNAs and what triggers their specific expression in germ cells?
We hope to address these questions with molecular, cell biology, and biochemical approaches in specific model systems, such as Xenopus oocytes, a repository and “living test tube” of Piwi proteins and piRNAs. Insights we gain from piRNA studies will complement our examinations of other RNAi pathways, like microRNAs and endo-siRNAs. We will apply our current biochemical techniques to probe the functional activity of the piRNA Complex, and develop genetic and cell biology methodologies to understand the role of piRNA clusters.
Our investigation of piRNA function and regulation of piRNA expression may impact our understanding of stem cells and regeneration. For example, transposable element control in germ cells versus transposon regulation in somatic cells might inform on the differences in pluripotency between germline stem cells and somatic stem cells. Perhaps epigenetic programming events during gametogenesis via small RNAs help to establish chromatin conformations necessary for proper embryogenesis. Notably, animals with extraordinary regenerative capacities, like planarians, utilize a pool of special stem cells that depend upon Piwi proteins and piRNAs for their survival. Understanding how Piwi proteins and piRNAs modulate gene expression may offer clues to the conceptual immortality that these animals possess.