Cancer is a disease often caused by dysregulated expression of oncogenes or tumour suppressor genes. One of the fundamental mechanisms that regulate global gene expression is through post-translational modification of histone proteins. In the context of the human genome, DNA is complexed with histone to form nucleosomes and chromatin. This functional organization of the genome is tightly regulated such that only appropriate genes are maintained in an open context that is accessible by transcription factors and RNA polymerases. In contrast, inactive genes are sequestered into compact structures and are transcriptionally silenced. Histone modifications regulate the balance between these open and closed chromatin states and define the gene expression profile of the functional genome.

Our lab utilizes a combination of molecular biology and biochemistry techniques to dissect the mechanisms of how histones and histone modifications regulate gene functions. Our projects are broadly divided into 2 main interests: 1) how signal transduction pathways converge onto histones to regulate gene functions, and 2) how histone variants function in the epigenetic regulation of gene expression.

For the first interest, we focus on the role of histone H3 phosphorylation in gene activation. Upon growth factor stimulation, the activated MAP kinase pathway ultimately converges onto chromatin and results in the phosphorylation of H3 at two specific serine resides (S10 and S28). The phosphorylation events are rapid and transient, and mirror the transcriptional activation of genes such as c-fos and c-jun. We are currently examining how H3 phosphorylation leads to transcriptional activation and we are testing whether these modifications recruit or repel regulatory factors to the c-fos and c-jun promoters. Our previous work also showed that H3 phosphorylation promotes acetylation on the same histone and these modifications function together to activate gene expression. The idea that histone modifications work in combinations was formally described as the Histone Code Hypothesis, and we are currently developing new techniques to dissect the intricate interplay between histone modifications in vivo and to test the validity of this hypothesis.

For the second interest, we are studying the functional role of an H2A variant, H2A.Z, in the regulation of gene expression. H2A.Z is essential for cell viability in that loss of H2A.Z function in mammalian cells leads to cell death or senescence. H2A.Z is localized to the transcription start sites of genes, and cumulative evidence suggests that this variant has both positive and negative regulatory functions in the gene expression process. We have found that a fraction of H2A.Z is modified by the addition of a single ubiquitin group and such modified H2A.Z is associated with transcriptionally silenced heterochromatin. We are currently testing how addition or removal of the ubiquitin modification on H2A.Z regulates transcription and gene expression.

Additional Appointments

• Canada Research Chair in Chromatin Regulation

Dr. Peter Cheung's Lab