Research

Epigenetic alterations and genome instability are hallmarks of aging and cancer but their molecular interdependency remains largely unknown. For example, gene activity and their regulation change with age, however, underlying relationships with epigenome structural alterations and genome instability, and their impact on aging and related disease development remain to be determined. Our lab aims to address four conceptual questions: 

1. Are epigenome structural alterations passengers or drivers of mammalian aging and disease?
2. Will particular epigenome structural states promote genome instability and disease development?
3. Can age-related epigenome alterations be suppressed and prolong mammalian tissue fitness? 
4. Are defined epigenome states of diagnostic and therapeutic value?

We are developing and employing genomics technologies to address these questions. 

Existence of epigenome structural alterations that significantly impact normal mammalian tissue aging.

Epigenetic alterations and genome instability are hallmarks of aging. We want to understand their relationship during normal tissue aging and regeneration. We are investigating epigenome alterations in different but closely-related mouse strains. We employ genome engineering tools to address molecular relationships of epigenome alterations with genome stability, and their impact on tissue aging and regeneration. 

(Epi)Genome structure and stability in premature ageing diseases.

Progeria patients, such as the Hutchinson-Gilford-Progeria-Syndrome (HGPS), rapidly age due to a precise genetic alteration, leading to the accumulation of epigenome alterations and instability. Our lab explores the relationship of (Epi)Genome structure and stability in rapid aging models and relates these findings to normal mammalian aging and associated disease development. 

(Epi)Genome structural alterations predisposing to cancer development and/or drug resistance.

Response and resistance to anticancer therapies vary owing to inter- and intra-tumour heterogeneity. Aberrant gene activity and genome instability are critical processes in cancer development. Precision medicine aims to characterise tumour heterogeneity and identify cancer-specific molecular vulnerabilities. Mutational signatures of lung cancer have been extensively characterised, but the impact of epigenome alterations and stability are less understood. Our lab aims to uncover epigenome alterations that critically drive lung cancer and resistance mechanisms using our recently established quantitative ChIP-seq technology to stratify patient-derived cancer xenograft models, reflecting on personalised genome architecture, transcription factor regulation and activity, as well as cancer subtypes suitable for drug-treatment.