Life Sciences Research for Lifelong Health

Peter Rugg-Gunn

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) in combination with a variety of molecular and genetic approaches to characterise and perturb their epigenomes. The stem cell models are sometimes complemented with the characterisation of mouse and human embryos at very early stages in their development.

This research is important because establishing our epigenomes correctly during development has long lasting consequences on our health, and we 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 abilitiy to drive their specialisation towards useful cell types, which are essential requirements to fulfill their promise in regenerative medicine. 

Latest Publications

Assessing the Safety of Human Pluripotent Stem Cells and Their Derivatives for Clinical Applications.
Andrews PW, Ben-David U, Benvenisty N, Coffey P, Eggan K, Knowles BB, Nagy A, Pera M, Reubinoff B, Rugg-Gunn PJ, Stacey GN

Pluripotent stem cells may acquire genetic and epigenetic variants during culture following their derivation. At a conference organized by the International Stem Cell Initiative, and held at The Jackson Laboratory, Bar Harbor, Maine, October 2016, participants discussed how the appearance of such variants can be monitored and minimized and, crucially, how their significance for the safety of therapeutic applications of these cells can be assessed. A strong recommendation from the meeting was that an international advisory group should be set up to review the genetic and epigenetic changes observed in human pluripotent stem cell lines and establish a framework for evaluating the risks that they may pose for clinical use.

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Stem cell reports, 9, 2213-6711, 1-4, 2017

PMID: 28700896

Transcriptional response of Hoxb genes to retinoid signalling is regionally restricted along the neural tube rostrocaudal axis.
Carucci N, Cacci E, Nisi PS, Licursi V, Paul YL, Biagioni S, Negri R, Rugg-Gunn PJ, Lupo G

During vertebrate neural development, positional information is largely specified by extracellular morphogens. Their distribution, however, is very dynamic due to the multiple roles played by the same signals in the developing and adult neural tissue. This suggests that neural progenitors are able to modify their competence to respond to morphogen signalling and autonomously maintain positional identities after their initial specification. In this work, we take advantage of in vitro culture systems of mouse neural stem/progenitor cells (NSPCs) to show that NSPCs isolated from rostral or caudal regions of the mouse neural tube are differentially responsive to retinoic acid (RA), a pivotal morphogen for the specification of posterior neural fates. Hoxb genes are among the best known RA direct targets in the neural tissue, yet we found that RA could promote their transcription only in caudal but not in rostral NSPCs. Correlating with these effects, key RA-responsive regulatory regions in the Hoxb cluster displayed opposite enrichment of activating or repressing histone marks in rostral and caudal NSPCs. Finally, RA was able to strengthen Hoxb chromatin activation in caudal NSPCs, but was ineffective on the repressed Hoxb chromatin of rostral NSPCs. These results suggest that the response of NSPCs to morphogen signalling across the rostrocaudal axis of the neural tube may be gated by the epigenetic configuration of target patterning genes, allowing long-term maintenance of intrinsic positional values in spite of continuously changing extrinsic signals.

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Royal Society open science, 4, , 160913, 2017

PMID: 28484611

Comprehensive Cell Surface Protein Profiling Identifies Specific Markers of Human Naive and Primed Pluripotent States.
Collier AJ, Panula SP, Schell JP, Chovanec P, Plaza Reyes A, Petropoulos S, Corcoran AE, Walker R, Douagi I, Lanner F, Rugg-Gunn PJ

Human pluripotent stem cells (PSCs) exist in naive and primed states and provide important models to investigate the earliest stages of human development. Naive cells can be obtained through primed-to-naive resetting, but there are no reliable methods to prospectively isolate unmodified naive cells during this process. Here we report comprehensive profiling of cell surface proteins by flow cytometry in naive and primed human PSCs. Several naive-specific, but not primed-specific, proteins were also expressed by pluripotent cells in the human preimplantation embryo. The upregulation of naive-specific cell surface proteins during primed-to-naive resetting enabled the isolation and characterization of live naive cells and intermediate cell populations. This analysis revealed distinct transcriptional and X chromosome inactivation changes associated with the early and late stages of naive cell formation. Thus, identification of state-specific proteins provides a robust set of molecular markers to define the human PSC state and allows new insights into the molecular events leading to naive cell resetting.

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Cell stem cell, , 1875-9777, , 2017

PMID: 28343983

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Keywords

developmental biology
epigenetics
pluripotency
stem cells

Group Members

Latest Publications

Assessing the Safety of Human Pluripotent Stem Cells and Their Derivatives for Clinical Applications.

Andrews PW, Ben-David U, Benvenisty N

Stem cell reports
9 2213-6711:1-4 (2017)

PMID: 28700896

Global reorganisation of cis-regulatory units upon lineage commitment of human embryonic stem cells.

Freire-Pritchett P, Schoenfelder S, Várnai C

eLife
6 2050-084X: (2017)

PMID: 28332981

Derivation and Culture of Epiblast Stem Cell (EpiSC) Lines.

Rugg-Gunn P

Cold Spring Harbor protocols
2017 1559-6095:pdb.prot093971 (2017)

PMID: 28049783

Derivation and Culture of Extra-Embryonic Endoderm Stem Cell Lines.

Rugg-Gunn P

Cold Spring Harbor protocols
2017 1559-6095:pdb.prot093963 (2017)

PMID: 28049782

Crosstalk between pluripotency factors and higher-order chromatin organization.

Lopes Novo C, Rugg-Gunn PJ

Nucleus (Austin, Tex.)
1949-1042:0 (2016)

PMID: 27759487

Comparative Principles of DNA Methylation Reprogramming during Human and Mouse In Vitro Primordial Germ Cell Specification.

von Meyenn F, Berrens RV, Andrews S

Developmental cell
39 1878-1551:104-115 (2016)

PMID: 27728778