OUR RESEARCH

We use the power of functional genetics and genomics in C. elegans to address fundamental questions in chromatin regulation and transcriptional control. Chromatin is the organization of genomic DNA and histones that can have a wide range of post-translational modifications along with hundreds of associated proteins and RNAs. The composition and structure of chromatin determines activity state and is central to the control of transcription, the expression of cell identity, the maintenance of pluripotency, and the transformation to cancer. However, our knowledge of chromatin composition and understanding of chromatin regulator function is still at a basic level. C. elegans has a complement of core chromatin factors very similar to that of humans (many with existing mutants), a small well-annotated genome (30x smaller than human), RNAi for loss of function studies, and well-characterised cell fates.

We combine wet-lab and computational approaches to a range of problems in chromatin biology and transcriptional control, such as genome organization, promoter and enhancer function, roles of histone modifications, heterochromatin formation and function, and the regulation of chromatin in developmental transitions.

Genome organization

The genome is organized into domains of different structure and activity. At a local level, genomic regions of similar activity harbor a shared chromatin composition, termed chromatin state. At larger scales, chromatin is organized into structural and/or activity domains.

Characterization and functional analysis of promoters, enhancers, and non-coding RNAs.

To regulate transcription, chromatin factors must impact the activities of promoters and enhancers, for example through altering their accessibility. Enhancers are classically bound by sequence-specific transcription factors that either activate or repress transcription from nearby core promoters.

Histone modifications and heterochromatin

A large number of post-translational modifications (PTMs) of histones occur in chromatin and individual modifications are highly associated with different activity states and gene features. However, the functions of most modifications in animals is incomplete or unknown and the enzymes directing particular modifications have not been comprehensively identified. We are studying mutants lacking particular histone modifications and of factors associated with modifications to determine their functional relevance.

Chromatin regulatory complexes implicated in human disease

Chromatin regulatory proteins are the workhorses of genome management, directing local transcription activation and repression as well as larger scale regulation. This involves many integrated processes, including nucleosome remodelling, histone modification and replacement, the binding of specific factors to accessible DNA or modified histones, and the organization of chromosome regions into domains.