Epigenetics helps define current cell states, yet also shapes how cells respond to external cues such as differentiation or stress.

The epigenetic plasticity of a cell describes how flexible this regulation is. Early embryonic cells are highly plastic in that they are able to generate all adult cell types. As development progresses, this plasticity is lost as normal healthy adult cells are locked in their identity. Crucially, aberrant reactivation may contribute to pathologies such as cancer. Importantly, we lack a comprehensive molecular understanding of epigenetic plasticity and how it is regulated. This knowledge will be invaluable in opening new avenues for cancer prognostic and therapeutic interventions.

It is increasingly apparent that epigenetic aberrations contribute to all aspects of cancer biology. Cancers often display features of heightened epigenetic plasticity, although what this entails precisely at the molecular level is still being untangled. Hyper-plasticity would confer cancer cells with adaptive advantages as they are readily able adapt to changing environments or therapies, promoting metastasis and relapse. For example, epigenetic hyper-plasticity may underly lineage infidelity, where cancers reappear after treatment as genetically identical yet functionally distinct pathologies, or acquired drug resistance. It is unknown the extent epigenetic hyper-plasticity occurs in cancers, how this manifests at a molecular level, and the significance this has on cancer progression and response to therapy. Our lab uses insights from developmental epigenetics to understand how the normal tight control of epigenetic plasticity is hijacked by cancers, using single-cell epigenomic, CRISPR and molecular cell biology technologies.

Research projects

Hijacking developmental epigenetic plasticity in cancers

Epigenetic plasticity of the chromatin and DNA methylation landscapes impacts the ease by which a cell can initiate new transcriptional programmes in response to external cues such as differentiation signals or changes in its environment. In stem cells, increased epigenetic plasticity is reflected by specific chromatin landscapes and transcriptional profiles. We are using these signatures to determine the prevalence of epigenetic plasticity in cancers and how these impact patient outcomes.

Dynamics and regulation of bivalent chromatin during cell state transitions

Bivalent chromatin is a unique epigenetic state characterised by coincident active and repressive histone modifications at gene promoters. It is postulated that bivalent chromatin keeps these promoters poised and amenable for future activation. While bivalent chromatin has been implicated in cancers the majority of our understanding comes from embryonic stem cells. We are developing new high-resolution methods to profile bivalent chromatin at high-molecular resolution and also in live single-cells to accurately map the dynamics and distribution of this chromatin state and uncover its regulation, resolution and significance on cell state transitions in both development and cancer models.

Discovery of novel epigenetic priming factors

Epigenetic priming factors are responsible for setting up a permissive epigenetic landscape early in development that is not required until later timepoints. We identified Dppa2 and Dppa4 as epigenetic priming factors in stem cells. Here they are required to establish a permissive chromatin landscape at key developmental promoters, poising them for future gene activation during differentiation. We are using high-throughput screens to discover new epigenetic priming factors in stem cells and cancer cells. We then apply classical and emerging new cell and molecular biology techniques to uncover how they function mechanistically.

Cancer cell plasticity and clonal heterogeneity

Cancer cells are dynamic and heterogeneous and contain subpopulations of highly plastic cells that are more aggressive and resistant to therapies. Cells can cycle in and out of this hyper-plastic state, however we do not know how or why these cellular transitions take place. Intriguingly individual cells can become locked into either the hyper- or hypo-plastic state and retain this memory for over 100 days. We are investigating the cell-intrinsic and cell-extrinsic mechanisms driving individual clone dynamics. This has important consequences for cancer evolution and adaptation, potentially impacting disease progression and patient outcomes.


Katie Fennell, Postdoctoral Researcher
Janith Seneviratne, Postdoctoral Researcher
Eleanor Glancy, Postdoctoral Researcher
William Ho, Research Assistant
Tongtong Wang, PhD Student
Will Sluman, Undergraduate Placement Student

Key publications

Kubinyecz O, Santos F, Drage D, Reik W and Eckersley-Maslin MA (2021) Maternal Dppa2 and Dppa4 are dispensable for zygotic genome activation but important for offspring survival. Development 148(24):dev200191

Alda-Catalinas C, Eckersley-Maslin MA and Reik W (2021) Pooled CRISPR-activation screening coupled with single-cell RNA-seq in mouse embryonic stem cells. STAR Protoc. 2(2):100426

Eckersley-Maslin MA (2020) Keeping your options open: insights from Dppa2/4 into how epigenetic priming factors promote cell plasticity. Biochemical Society Transactions 48(6):2891-2902

Eckersley-Maslin MA*, Parry A, Blotenberg M, Krueger C, Ito Y, Franklin VNR, Narita M, D’Santos C and Reik W*. (2020) Dppa2 and Dppa4 target chromatin bivalency enabling multi-lineage commitment. Nature Structural and Molecular Biology. 27(8):696-70 *Co-corresponding author

Alda-Catalinas C, Bredikhin D, Harnando-Herraez I, Eckersley-Maslin MA*, Stegle O* and Reik W*. (2020) A single-cell transcriptomics CRISPR-activation screen identifies new epigenetic regulators of zygotic genome activation, Cell Systems. 11(1):25-4 *Co-senior and co-corresponding author

Eckersley-Maslin MA* ^, Alda-Catalinas C* ^, Reik W*. (2018) Dynamics of the epigenetic landscape during the maternal-to-zygotic transition. Nat Rev Mol Cell Biol 19(7):436-450 * co-corresponding author ^ co-first author

Research programs