The regulation of chromatin structure and function. (360G-Wellcome-101863_Z_13_Z)

We will use the power of functional genetics and genomics in C. elegans to address fundamental questions in chromatin regulation and transcriptional control, by analysing epigenetic state and function in wild-type and mutant animals and tissues. Chromatin is the organization of genomic DNA with histones that can have a wide range of post-translational modifications and 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 will combine the strengths of model organism genetics with genome-wide chromatin phenotyping to unravel mechanisms of chromatin regulation that will have impact across animals. Our specific aims: 1. More comprehensively characterize properties of wild-type chromatin and discover regulatory principles that operate in cell fate determination and differentiation. 2. Use global chromatin phenotype profiling of mutants to unravel functions and mechanisms of action of conserved chromatin regulators important for human biology. 3. Profile transcription initiation and elongation to investigate the developmental regulation of promoters, enhancers, and non-coding transcription, and use transgene constructs for their functional analyses.