Dónal O'Carroll (FRSE FRS)

  • Centre for Cell Biology

Contact details

Address

Street

Centre for Cell Biology,
School of Biological Sciences,
The University of Edinburgh,
5.27 Michael Swann Building,
Max Born Crescent,

City
Edinburgh
Post code
EH9 3BF

Biography

Background

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 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 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. In recognition of his contribution to research, he was elected a Fellow of the Royal Society of Edinburgh (2019), a Member of the European Molecular Biology Organisation (2020) and a Fellow of the Royal Society (2025). Dónal is currently the Associate Director of the Centre for Cell Biology.

Open to PhD supervision enquiries?

Yes

Research summary

Mechanisms of germline integrity and fitness.

Our research explores the molecular mechanisms of regulatory RNA pathways in germline anti-transposon immunity, development, longevity, and ageing. 

 

Overview

The germline is the ancient cell lineage that gives rise to the gametes. It is responsible for the propagation and continuity of life. The germline directly connects animal species across evolutionary history and is thus also known as the immortal lineage. Germline immortality is of paramount importance for life. This immortality comes at a cost: the necessity to establish, maintain, protect, and repair the germline. The male and female germline physiologies are incredibly different. The male germline operates as a vastly expansive system that relies on the generation of nearly infinite numbers of gametes from stem cells. The mammalian female germline, once generated, yields a finite number of oocytes. This pool of primordial oocytes constitutes the oocyte reserve that supports fertility and defines the reproductive lifespan. The germline is especially vulnerable to the activity of transposons. Active transposons pose an existential threat to the continuity of the germline through transposition-associated DNA damage and mutation. The O’Carroll laboratory studies the basis of germline anti-transposon immunity and regulatory RNA pathways that sustain female fertility.

 

The piRNA Pathway

In mammals, the acquisition of the germline from the soma provides the germline an essential challenge: the necessity to erase and reset genomic methylation. The loss of DNA methylation unleashes transposon expression with the potential to annihilate the germline. The PIWI-interacting pathway (piRNA) pathway provides anti-transposon immunity. At the core of this pathway are the piRNAs and the PIWI proteins. piRNAs are short non-coding RNAs that are bound to PIWI proteins, which are members of the Argonaute protein family. Through base complementarity, piRNAs act as guides to recruit the PIWI proteins to cellular RNAs. In the cytoplasm, piRNAs guide PIWI-mediated cleavage of transposon transcripts through an RNAi-like mechanism to suppress transposition (Figure 1). In the nucleus, the piRNA pathway mediates transcriptional silencing of transposons through DNA methylation (Figure 1).

 

piRNA loading

The loading of precursor-piRNAs into PIWI proteins and subsequent processing to mature piRNAs are central to the function of the pathway. piRNA biogenesis takes place in the nuage, germ cell-specific membrane-less structures found in the cytoplasm often in the proximity of mitochondria. Our current goal is to understand the mechanism by which precursor-piRNAs are selected and loaded into PIWI proteins for processing.

 

piRNA-directed transposon DNA methylation

Antisense transposon-derived piRNAs guide the nuclear PIWI protein, MIWI2, to instruct transposon DNA methylation. piRNAs tether MIWI2 to the active transposon loci by base pairing to nascent transcripts. We have found the first effectors of nuclear MIWI2 function: SPOCD1, C19ORF84, SPIN1, and TEX15. SPOCD1 is a molecular scaffold and together with the adaptor protein C19ORF84 connects MIWI2 to the de novo methylation machinery (Nature 2020 and Mol Cell 2024) (Figure 1). The molecular function of TEX15 remains unknown. We found that active LINE1 transposon copies are marked with a unique set of chromatin modifications that recruit SPOCD1 through the chromatin reader SPIN1. This is the foundation for a two-factor authentication process that prevents off-targeting or autoimmunity (Nature2024). Our current goal is to fully understand the mechanism of piRNA-directed DNA methylation.

 

Evolution of germline anti-transposon immunity

The piRNA pathway is found throughout metazoan life. The cytoplasmic pathway is ancient. The nuclear pathway is less conserved and has evolved several times during metazoan evolution. The nuclear piRNA pathway that mediates transposon DNA re-methylation in mice is believed to be bespoke to mammals. However, we found that Anolis SPOCD1 can interact with SPIN1 through the same mechanism as the mouse SPOCD1-SPIN1 interaction (Nature 2024). This hints to an origin for the piRNA-directed DNA methylation early in tetrapod evolution. Our future goal is to understand the origin of the mammalian nuclear piRNA pathway.

 

Regulatory RNA pathways in the female germline

Oocyte maturation, fertilisation and early zygotic development occur in the absence of transcription. As such, maternal RNA is the blueprint for early life. The maternal RNA repertoire and levels, as well as their ordered usage and decay are essential for life. We found that RNA modification plays a crucial role in building the maternal transcriptome (Nature2017) and its programmed elimination. Primordial oocytes, that constitute the oocyte reserve, survive for long periods due to their metabolically dormant state. It is not known how these oocytes can maintain RNA and protein levels and patterns for these exceptionally long periods. Our future goal is to understand how regulatory RNA pathways contribute to oocyte longevity and reproductive lifespan.

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