Professor of Stem Cell Biology and Wellcome Senior Investigator
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. Since 2015 he has been 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 approaches to explore the PIWI-interacting RNA (piRNA) and RNA modification pathways.
Regulation of gene expression by non-coding RNA and RNA modification
My laboratory has a longstanding interest in RNA-based mechanisms that regulate gene expression and epigenetic transposon silencing in the mammalian germline. Currently, our research explores the contribution of PIWI-interacting RNA (piRNA) and RNA modification pathways to germ cell development.
The piRNA pathway. 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. De novo genome methylation re-encodes the epigenome, imprinting and transposable element (TE) silencing. In the male germline piRNA-directed DNA methylation silences young active TEs. This poorly understood but essential process is central to the immortality of the germline. Upon completion of germline reprogramming with the full erasure of genomic methylation, TEs become derepressed. PIWI proteins, MILI & MIWI2, and their associated piRNAs neutralise this threat. Firstly, piRNAs guide the PIWI endonuclease MILI through base complementarity 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 by an unknow mechanism. We have made important contributions to the mechanism of piRNA biogenesis as well as elucidating the functions of the piRNA pathway during adult spermatogenesis. Our current goal is to understand the elusive mechanism by which MIWI2 instructs TE methylation and epigenetic silencing (Figure A).
RNA modification. Several stages of both male and female germ cell development are transcriptionally inert and thus rely on post-transcriptional regulation of gene expression. Therefore, the study of RNA modification in the germline will likely give profound insights into both processes. We focus on the function of N6-methyladenosine (m6A) and 3' terminal uridylation mRNA modifications, both of which can promote RNA degradation. We showed essential and specific functions for poly(A) tail length and TUT4/7-mediated 3' terminal uridylation in sculpting a functional maternal transcriptome during oocyte growth (Nature 2017) (Figure B). We recently demonstrated that a programmed wave of uridylation-primed mRNA degradation is essential for meiotic progression and mammalian spermatogenesis (Cell Res 2019). We demonstrated that the m6A-reader YTHDF2 regulates transcript dosage during oocyte maturation and is an intrinsic determinant of mammalian oocyte competence as well as early zygotic development (Mol Cell 2017) (Figure B). Finally, we have shown that the m6A-reader YTHDF2 is overexpressed in multiple sub-types of AML and its deletion selectively compromises cancer stem cells, in mouse AML models and human primary samples, without grossly perturbing normal haematopoiesis (Cell Stem Cell, 2019). We are currently exploring basic questions about the mechanism, function and redundancy of YTH domain m6A readers.
Paris J, Morgan M, Campos J, Spencer GJ, Shmakova A, Ivanova I, Mapperley C,Lawson H, Wotherspoon DA, Sepulveda C, Vukovic M, Allen L, Sarapuu A, Tavosanis A, Guitart AV, Villacreces A, Much C, Choe J, Azar A, van de Lagemaat LN,Vernimmen D, Nehme A, Mazurier F, Somervaille TCP, Gregory RI, O'Carroll D*, Kranc KR*. Targeting the RNA m(6)A Reader YTHDF2 Selectively Compromises Cancer Stem Cells in Acute Myeloid Leukemia. Cell Stem Cell. 2019 Apr 24. pii:S1934-5909(19)30120-1. doi: 10.1016/j.stem.2019.03.021. [Epub ahead of print] PubMed PMID: 31031138. * co-corresponding authors
Morgan M, Kabayama Y, Much C, Ivanova I, Di Giacomo M, Auchynnikava T, Monahan JM, Vitsios DM, Vasiliauskaite L, Comazzetto S, Rappsilber J, Allshire RC, Porse BT, Enright AJ, O'Carroll D. A programmed wave of uridylation-primed mRNA degradation is essential for meiotic progression and mammalian spermatogenesis. Cell Res. 2019 Jan 7. doi: 10.1038/s41422-018-0128-1. [Epub ahead of print] PubMed PMID: 30617251.
Vasiliauskaite L, Berrens RV, Ivanova I, Carrieri C, Reik W, Enright AJ, O'Carroll D. Defective germline reprogramming rewires the spermatogonial transcriptome. Nat Struct Mol Biol. 2018 May;25(5):394-404. doi:10.1038/s41594-018-0058-0. Epub 2018 Apr 30. PubMed PMID: 29728652.
A. Genomic DNA methylation is erased (reprogramming) and reset (de novo methylation) during germ cell development. The mechanism by which the PIWI protein MIWI2 direct de novo methylation of young transposable elements remains unknown.
B. TUT4/7-mediated 3' terminal mRNA uridylation is required to build a functional maternal transcriptome during oocyte growth whereas m6A-YTHDF2 is required for the metabolism of maternal transcripts during oocyte maturation. Both modifications are essential for oocyte competence and fertility.