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.
Dynamics of epigenetic plasticity in cancers at single-cell resolution
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 generates a specific transcriptional profile. We are using this signature to determine the prevalence of epigenetic plasticity in cancers using single-cell technologies and profiling those cells with heightened plasticity. Our aim is to uncover the dynamics of epigenetic plasticity in human cancers and its significance for patient outcomes.
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 new CRISPR-based single-cell assays 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.
Functional significance of altering epigenetic plasticity
Somewhat surprisingly, many of the transcripts associated with increased epigenetic plasticity are completely uncharacterised. We are exploring the expression dynamics of these transcripts at single-cell resolution in development and cancers, linking this with patient outcome to find new prognostic biomarkers. Mechanistic and functional experiments are uncovering the biological roles of these transcripts in both a developmental and cancer context.
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