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

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

Global reorganisation of cis-regulatory units upon lineage commitment of human embryonic stem cells.
Freire-Pritchett P, Schoenfelder S, Várnai C, Wingett SW, Cairns J, Collier AJ, García-Vílchez R, Furlan-Magaril M, Osborne CS, Fraser PJ, Rugg-Gunn PJ, Spivakov M

Long-range cis-regulatory elements such as enhancers coordinate cell-specific transcriptional programmes by engaging in DNA looping interactions with target promoters. Deciphering the interplay between the promoter connectivity and activity of cis-regulatory elements during lineage commitment is crucial for understanding developmental transcriptional control. Here, we use Promoter Capture Hi-C to generate a high-resolution atlas of chromosomal interactions involving ~22,000 gene promoters in human pluripotent and lineage-committed cells, identifying putative target genes for known and predicted enhancer elements. We reveal extensive dynamics of cis-regulatory contacts upon lineage commitment, including the acquisition and loss of promoter interactions. This spatial rewiring occurs preferentially with predicted changes in the activity of cis-regulatory elements, and is associated with changes in target gene expression. Our results provide a global and integrated view of promoter interactome dynamics during lineage commitment of human pluripotent cells.

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eLife, 6, 2050-084X, , 2017

PMID: 28332981

DNA methylation is dispensable for changes in global chromatin architecture but required for chromocentre formation in early stem cell differentiation.
Hassan-Zadeh V, Rugg-Gunn P, Bazett-Jones DP

Epiblast stem cells (EpiSCs), which are pluripotent cells isolated from early post-implantation mouse embryos (E5.5), show both similarities and differences compared to mouse embryonic stem cells (mESCs), isolated earlier from the inner cell mass (ICM) of the E3.5 embryo. Previously, we have observed that while chromatin is very dispersed in E3.5 ICM, compact chromatin domains and chromocentres appear in E5.5 epiblasts after embryo implantation. Given that the observed chromatin re-organization in E5.5 epiblasts coincides with an increase in DNA methylation, in this study, we aimed to examine the role of DNA methylation in chromatin re-organization during the in vitro conversion of ESCs to EpiSCs. The requirement for DNA methylation was determined by converting both wild-type and DNA methylation-deficient ESCs to EpiSCs, followed by structural analysis with electron spectroscopic imaging (ESI). We show that the chromatin re-organization which occurs in vivo can be re-capitulated in vitro during the ESC to EpiSC conversion. Indeed, after 7 days in EpiSC media, compact chromatin domains begin to appear throughout the nuclear volume, creating a chromatin organization similar to E5 epiblasts and embryo-derived EpiSCs. Our data demonstrate that DNA methylation is dispensable for this global chromatin re-organization but required for the compaction of pericentromeric chromatin into chromocentres.

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Chromosoma, , 1432-0886, , 2017

PMID: 28084535

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Keywords

developmental biology
epigenetics
pluripotency
stem cells

Group Members

Latest Publications

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