Regulation of chromatin structure plays a central role in transcriptional control. A large number of chromatin regulating enzymes and complexes have been identified that induce changes in gene activity through alterations in local and/or higher order chromatin structure, however their mechanisms of action and relationships are poorly understood. C. elegans has many features that make it especially well-suited for studies of chromatin regulation. It has a small well-annotated genome, powerful RNAi technology, and a rich resource of chromatin mutants for loss of function studies. In addition, C. elegans has a complement of chromatin factors very similar to that of humans, in contrast to yeast, and so allows investigations of chromatin function in a multicellular organism.
We are investigating the functions of C. elegans counterparts of major chromatin regulatory complexes that are implicated in human disease including the histone deacetylase complex NuRD, the Retinoblastoma complex DRM, and a TIP60 histone acetyltransferase complex. We study the function of these proteins in transcriptional control and development using chromatin immunoprecipitation and other genetic and genomic methods.
A chromatin “phenotype” we are using for studying functions for chromatin proteins are post-translational modifications to histone tails (e.g, methylation, acetylation, ubiquitination, and phosphorylation) because these reflect and modulate chromatin structure and function. To begin to provide a framework for analyses in C. elegans, we recently generated a genome-wide map of histone H3 tail methylations (Kolasinska et al, 2009). C. elegans genes show similarities in distributions of histone modifications to those of other organisms, with H3K4me3 near transcription start sites, H3K36me3 in the body of genes, and H3K9me3 enriched on silent genes. We discovered that exons are preferentially enriched with H3K36me3 relative to introns. H3K36me3 exon marking appears to be splicing related because its level is lower in alternatively spliced exons than in constitutive exons. The difference in H3K36me3 marking between exons and introns is evolutionarily conserved in human and mouse. We are currently studying the function of H3K36me3 exon marking and its relationship with splicing.
We are also part of a modENCODE consortium to map chromatin structure in C. elegans.
