Safeguarding Immortality

Prof Dónal O'Carroll; Centre for Regenerative Medicine & Wellcome Centre for Cell Biology

After graduating in biochemistry from Trinity College Dublin, Dónal O’Carroll performed his PhD studies in the laboratory of Thomas Jenuwein at the Research Institute for Molecular Pathology (IMP) in Vienna. Thereafter he joined The Rockefeller University as a postdoctoral fellow and research associate with Alexander Tarakhovsky. In 2007, Dónal moved to the European Molecular Biology Laboratory (EMBL) in Rome as a group leader. He joined the University of Edinburgh in 2015 as the Chair of Stem Cell Biology. Between 2015 and 2020, he was the Head of the Institute for Stem Cell Research and Associate Director of the Centre for Regenerative Medicine. In 2018 he also became a group leader at the Wellcome Centre for Cell Biology. The O’Carroll laboratory studies the mammalian germline from an RNA perspective. His laboratory couples advanced mouse genetics with state-of-the-art sequencing and proteomic approaches to explore the PIWI-interacting RNA (piRNA) pathway, RNA modification and germ cell ageing. He has made many discoveries that have contributed to the understanding of transcriptional and post-transcriptional mechanisms that regulate gene and transposon expression.

In mammals, the acquisition of the germline from the soma provides the germline with an essential challenge, the necessity to erase and reset genomic methylation. In the male germline piRNA-directed DNA methylation silences young active transposable elements (TEs). Firstly, through base complementarity piRNAs guide the PIWI endonuclease MILI to destroy cytoplasmic transposon RNAs. Secondly, antisense TE-derived piRNAs generated from intricate biogenesis pathways act to guide the nuclear PIWI protein MIWI2 to instruct TE DNA methylation. We have recently revealed the first molecular insights into these processes by defining MIWI2 interactomes in foetal gonads. We identified two MIWI2-associated nuclear factors, TEX15 and SPOCD1, that are essential for piRNA-directed de novo TE methylation. SPOCD1 links MIWI2 to components of the de novo methylation machinery. The mechanisms by which MIWI2 and SPOCD1 instruct TE methylation and epigenetic silencing will be presented.