Active Genetics & Molecular Biology Cells, Biochemistry & Physiology

Evolutionary epigenetics of X-chromosome inactivation

Funder Wellcome Charity-funded
Recipient organisation The Francis Crick Institute
Funding £2.0M
Period Jan 2022 — Dec 2026

In plain English

AI plain-English summary

Every cell in a woman’s body has silenced one of its two X chromosomes, and scientists still don’t fully understand how. This project uses opossums—marsupials that split from placental mammals 160 million years ago—to uncover the ancient epigenetic machinery that controls this process. The core problem is that while researchers know the RNA molecule Xist silences the X chromosome in placental mammals, the precise mechanisms and how they evolved remain a black box. The team has already identified RSX and XSR, the marsupial equivalents of Xist and its regulator Tsix, giving them a powerful comparative system. This is fundamental science: it asks how epigenetic pathways shape development, pluripotency, and germline formation across mammals. There is no immediate clinical application. But understanding how an entire chromosome is switched on and off—and how that process evolved—could eventually inform therapies for X-linked disorders, cancer, and developmental conditions where epigenetic regulation goes awry. The project also marks the first use of genome editing in marsupials, a technical advance that could accelerate research in cancer biology, neurobiology, and infectious disease.

View original technical description
How epigenetic pathways regulate development and disease remains a major question in human biology. A remarkable paradigm for understanding epigenetic mechanisms is X-chromosome inactivation, the silencing of one X chromosome in females (XX) that equalises X-dosage with males (XY). X-inactivation in eutherian (placental) mammals is mediated by the non-coding RNA (ncRNA) Xist. How Xist silences the X chromosome, and how expression of Xist is regulated, remain poorly understood. Marsupials diverged from eutherian (placental) mammals 160 million years ago, and exhibit distinctive developmental features that make them ideal for studying development and disease. Using our colony of opossums, we identified RSX and XSR, the marsupial equivalents of Xist and Tsix, providing a comparative system for understanding RNA-mediated chromatin remodelling. In this proposal, we will deploy the opossum model system to identify deeply conserved epigenetic mechanisms regulating mammalian X-inactivation and X-chromosome reactivation, and to elucidate how they interface with global epigenomic changes in the early embryo and germline. Our datasets will shed light on the evolution of mammalian lineage specification, pluripotency, imprinting and germline development. We will apply genome editing to marsupials for the first time, accelerating discovery in other research fields, including cancer biology, neurobiology and infectious disease.

View the original record at the funder ↗

Researchers

James Turner (EPMC Awardee)

Related Research

Grants with similar aims, by meaning.

Role of epigenetic mechanisms in random X chromosome inactivation ex vivo and in vivo.
Single cell profiling of X chromosome reactivation during primordial germ cell specification in vivo
Dissecting Chromatin Dynamics in X Chromosome Inactivation and Early Development
Regulation of the X chromosome in pluripotency, development and disease
Mechanisms of gene silencing in X chromosome inactivation.

Original classification

Investigator Award in Science

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