A 2026 Crick PhD project with Edith Heard.
Project background and description
Autosomal random monoallelic expression (aRME) is an epigenetic phenomenon in which only one allele of a gene is expressed in a given cell in a stable, clonal manner independent of parental origin. Initially thought to be rare, aRME is increasingly recognized as widespread in humans and mice. Work from the Heard lab has demonstrated that aRME is established during differentiation of pluripotent cells and can be stably propagated as in X-chromosome inactivation. How and why aRME occurs remains an exciting open question. During development, aRME could contribute to cellular heterogeneity and lineage choice. Importantly, aRME also has profound implications for human disease: by creating functional haploidy at the single-cell level, it can modulate penetrance, expressivity, and cell-to-cell variability in autosomal dominant disorders, including cardiovascular disease and neurodegeneration. The Heard lab has previously identified several aRME genes and established in vivo and in vitro models for their investigation. The project aims to investigate how aRME is established, maintained, or resolved during development, and how its misregulation may contribute to disease phenotypes. Understanding aRME will provide fundamental insight into gene regulation, developmental decision-making, and the origins of variability in dominant genetic disorders, in both males and females.
Candidate background
The candidate would preferably have knowledge and experience in genetics, biochemistry and/or molecular biology, though not essential. They should be interactive, and enjoy working in an open and collaborative environment.
References
- Hauth, A., Panten, J., Kneuss, E., … Heard, E. (2026) Escape from X inactivation is directly modulated by Xist noncoding RNA. Nat Cell Biol 28, 166–181. PubMed abstract
- Dossin, F., Pinheiro, I., Żylicz, J.J., Roensch, J., Collombet, S., Le Saux, A.,... Heard, E. (2020) SPEN integrates transcriptional and epigenetic control of X-inactivation. Nature 578: 455-460. PubMed abstract
- Gendrel, A.V, Attia, M., Chen, C.J., Diabangouaya, P., Servant, N., Barillot, E., Heard, E. (2014) Developmental dynamics and disease potential of random monoallelic gene expression. Dev Cell. 28, 366-80. PubMed abstract
- Marion-Poll, L., Forêt, B., Zielinski, D., Massip, F., Attia, M., Carter, A.C., Syx, L., Chang, H.Y., Gendrel, A.V., Heard, E. (2021) Locus specific epigenetic modalities of random allelic expression imbalance. Nat Commun. 12, 5330. PubMed abstract
- Stewart, O., Gruber, C., Randolph, H.E. et al. (2025) Monoallelic expression can govern penetrance of inborn errors of immunity. Nature 637, 1186–1197. PubMed abstract
