Rugg-Gunn Group

Rugg-Gunn Group
Rugg-Gunn Group
Peter Rugg-Gunn
Group Leader and Head of Public Engagement
Rugg-Gunn Group

Research Summary

We are interested in understanding how the epigenome is established during human development and stem cell differentiation, and how epigenetic information changes over the life course of a person.

To research these topics, we use different types of stem cell (primarily human pluripotent stem cells), stem cell-based embryo models (blastoids and gastruloids), and donated human embryos, in combination with a variety of molecular and genetic approaches to investigate their epigenomes.

This research is important because establishing our epigenomes correctly during development is vital for establishing a healthy pregnancy, and has long lasting consequences on our health. We therefore need to know more about how it happens and why it sometimes goes wrong. Our work also provides new avenues for improving the epigenetic stability of human pluripotent stem cells, and our ability to drive their specialisation towards useful cell types, which are essential requirements to fulfill their promise in regenerative medicine. 

Latest Publications

Novo CL, Wong EV, Hockings C, Poudel C, Sheekey E, Wiese M, Okkenhaug H, Boulton SJ, Basu S, Walker S, Kaminski Schierle GS, Narlikar GJ, Rugg-Gunn PJ

Heterochromatin maintains genome integrity and function, and is organised into distinct nuclear domains. Some of these domains are proposed to form by phase separation through the accumulation of HP1ɑ. Mouse heterochromatin contains noncoding major satellite repeats (MSR), which are highly transcribed in mouse embryonic stem cells (ESCs). Here, we report that MSR transcripts can drive the formation of HP1ɑ droplets in vitro, and modulate heterochromatin into dynamic condensates in ESCs, contributing to the formation of large nuclear domains that are characteristic of pluripotent cells. Depleting MSR transcripts causes heterochromatin to transition into a more compact and static state. Unexpectedly, changing heterochromatin's biophysical properties has severe consequences for ESCs, including chromosome instability and mitotic defects. These findings uncover an essential role for MSR transcripts in modulating the organisation and properties of heterochromatin to preserve genome stability. They also provide insights into the processes that could regulate phase separation and the functional consequences of disrupting the properties of heterochromatin condensates.

+view abstract Nature communications, PMID: 35725842 20 Jun 2022

Zijlmans DW, Talon I, Verhelst S, Bendall A, Van Nerum K, Javali A, Malcolm AA, van Knippenberg SSFA, Biggins L, To SK, Janiszewski A, Admiraal D, Knops R, Corthout N, Balaton BP, Georgolopoulos G, Panda A, Bhanu NV, Collier AJ, Fabian C, Allsop RN, Chappell J, Pham TXA, Oberhuemer M, Ertekin C, Vanheer L, Athanasouli P, Lluis F, Deforce D, Jansen JH, Garcia BA, Vermeulen M, Rivron N, Dhaenens M, Marks H, Rugg-Gunn PJ, Pasque V

Human naive pluripotent stem cells have unrestricted lineage potential. Underpinning this property, naive cells are thought to lack chromatin-based lineage barriers. However, this assumption has not been tested. Here we define the chromatin-associated proteome, histone post-translational modifications and transcriptome of human naive and primed pluripotent stem cells. Our integrated analysis reveals differences in the relative abundance and activities of distinct chromatin modules. We identify a strong enrichment of polycomb repressive complex 2 (PRC2)-associated H3K27me3 in the chromatin of naive pluripotent stem cells and H3K27me3 enrichment at promoters of lineage-determining genes, including trophoblast regulators. PRC2 activity acts as a chromatin barrier restricting the differentiation of naive cells towards the trophoblast lineage, whereas inhibition of PRC2 promotes trophoblast-fate induction and cavity formation in human blastoids. Together, our results establish that human naive pluripotent stem cells are not epigenetically unrestricted, but instead possess chromatin mechanisms that oppose the induction of alternative cell fates.

+view abstract Nature cell biology, PMID: 35697783 Jun 2022

Rostovskaya M, Andrews S, Reik W, Rugg-Gunn PJ Epigenetics, Bioinformatics

In primates, the amnion emerges through cavitation of the epiblast during implantation, whereas in other species it does so later at gastrulation by the folding of the ectoderm. How the mechanisms of amniogenesis diversified during evolution remains unknown. Unexpectedly, single-cell analysis of primate embryos uncovered two transcriptionally and temporally distinct amniogenesis waves. To study this, we employed the naive-to-primed transition of human pluripotent stem cells (hPSCs) to model peri-implantation epiblast development. Partially primed hPSCs transiently gained the ability to differentiate into cavitating epithelium that transcriptionally and morphologically matched the early amnion, whereas fully primed hPSCs produced cells resembling the late amnion instead, thus recapitulating the two independent differentiation waves. The early wave follows a trophectoderm-like pathway and encompasses cavitation, whereas the late wave resembles an ectoderm-like route during gastrulation. The discovery of two independent waves explains how amniogenesis through cavitation could emerge during evolution via duplication of the pre-existing trophectoderm program.

+view abstract Cell stem cell, PMID: 35439430 05 May 2022

Group Members

Peter Rugg-Gunn

Group Leader and Head of Public Engagement

Richard Acton

Data Outputs Manager

Adam Bendall

PhD Student

Louis Coussement

Visiting Student

Sarah Elderkin

Senior Research Scientist

Andrew Malcolm

Postdoc Research Scientist

Kate Maskalenka

PhD Student

Matteo Mole

Postdoc Research Scientist

Andrea Palomar

Visiting Scientist

Maria Rostovskaya

Senior Research Scientist

Maria Santos Romero

Postdoc Research Scientist

Yang Wang

Postdoc Research Scientist

Amy Wilkinson

PhD Student

Thomas Willday

Research Assistant

Irene Zorzan

Postdoc Research Scientist