Epigenetics is the study of heritable changes in gene expression (active versus inactive genes) that does not involve changes to the underlying DNA sequence. Recent genome-sequencing studies have uncovered mutations in a large cohort of chromatin regulators that are causally implicated in cancer as well as in various human developmental disorders. Furthermore, the emerging view that deleterious gene expression patterns observed in aging and age-related disorders are driven by persistent changes in chromatin structure, underscores an urgent need to evaluate the role of epigenetic processes in human health. We believe that exploring the epigenome will provide important insights into disease pathogenesis, as well as guide the identification of prognostic biomarkers and the development of new therapeutic targets.
Work in the lab may be broadly divided into three main areas: (1) Disease Epigenetics and (2) Chromatin Plasticity and Developmental Potency and (3) Technology Development.
Some of our key questions include:
- How is the epigenome established, dynamically modified, and transmitted to the next generation?
- How epigenetic factors interact with genetic variants and environmental cues to influence the pathogenesis of complex human diseases such as cancer, neurodegeneration and metabolic disorders?.
- How do we translate our understanding of epigenetic mechanisms to develop novel epigenetic-based diagnostics and therapies?
Unlike genetic mutations, epigenetic alterations are reversible. This presents a therapeutic opportunity to restore proper gene expression patterns and revert diseased phenotypes towards normality. A major effort in the lab is to investigate how transcriptional and chromatin aberrancies promote tumorigenesis and to identify new epigenetic targets in cancer. By performing integrative analyses of large scale cancer epigenomic data with genome and transcriptome sequencing data, we aim to obtain a comprehensive understanding of the complex architecture of cancer genomes, and to leverage epigenomic information for prognostic stratification of patients as well as predict treatment response.
We also have a keen interest to understand how epigenetic aberrancies underlie neurodegeneration and metabolic disorders (eg., Alzheimer's disease and Type-2 Diabetes). The escalating rates for many of these age-related disorders cannot be solely explained by genetic drift. In this regard, understanding how environmental factors impact epigenetic processes to influence disease outcomes is key to filling this fundamental knowledge gap. We are currently investigating how affected epigenetic pathways interact with genetic risk factors in Alzheimer’s and Parkinson's disease. To address these questions, we use human pluripotent cells to determine the functional causality of disease-associated variants, and utilise an assortment of molecular tools to interrogate epigenetic changes (eg., at the level of DNA and histone modifications, chromatin remodelling, non-coding RNA, as well as higher-order nuclear organization) during disease initiation and progression. Coupled with the use of cell-based screens, we aim to identify epigenetic agents that may exert neuroprotective effects.
Chromatin plasticity & DEVELOPMENTAL POTENCY
Distinct epigenetic and transcription factor complexes cooperate to instruct specific gene expression patterns, thereby supervising cell fate decisions. In the other major strand of research in the group, we are interested to explore the relationship between chromatin plasticity and cellular potency. For this, we utilise different experimental models of tissue regeneration and epigenetic reprogramming. The latter includes in vivo reprogramming events that occur during early embryogenesis and in the germline, as well as during induced pluripotency in vitro. Our objective is to uncover unifying principles of cellular reprogramming, and to leverage this knowledge to re-engineer cellular phenotypes at will through manipulation of chromatin structure and function, for regenerative medicine applications.
Our lab aims to develop novel tools and assays to probe and perturb epigenetic activity as a function of development and disease. To best understand the mechanistic ties between chromatin state, gene expression and cell phenotype, it is necessary to create molecular tools that will enable us to engineer the epigenome in a programmable manner, to direct specific changes in gene expression. The development of epigenomic-editing tools will enable us to selectively perturb or reconstruct aberrant gene regulatory networks associated with pathological states, and in doing so, identify potential therapies.