Chromatin is the complex of DNA and its intimately associated proteins -with histones constituting the major component. This template is an attractive candidate for shaping the features of a cell’s epigenetic landscape. Disruption of a cell’s epigenetic balance can perturb chromatin structure and gene regulation, contributing to disease states.
Our work focuses on the study of histone variant proteins. When incorporated into chromatin, histone variants participate in diverse nuclear functions including centromeric regulation, DNA damage responses, transcriptional activation and repression, and play a role in epigenetic inheritance of chromatin states. Histone variants alter the structure and stability of the nucleosome, and provide the cell with the potential to change its post-translational modification (PTM) profile due to amino acid sequence differences from their conventional histone counterparts. We are interested in variant-specific PTMs and their binding proteins, as well as the chaperones that escort these proteins in and out of the chromatin template. We have uncovered a critical suppressive role for the histone variant macroH2A in the progression of malignant melanoma. In addition to acting as a barrier to melanoma growth and metastasis, we reported that macroH2A also acts as a barrier to induced pluripotency by repressing a set of genes required for the early stages of reprogramming.
The Polycomb Group (PcG) proteins are also focus of the lab. In mammals, there are five homologs of the single Drosophila Pc protein and it has been a longstanding goal to understand the consequences of such expansion and diversification of this protein family in both development and disease. We have previously demonstrated that each individual Pc protein is unique not only in its histone binding-specificity, but also in its association with heterochromatin (in particular, the inactive X chromosome in female mammals). Recently, we identified Cbx7 as the primary Polycomb protein expressed in ESCs, which is important for maintaining pluripotency. We have also identified novel PTMs of Cbx family members.
Our long-term goal is to understand the chromatin changes that take place at the molecular level during the transformation process of ‘normal cells’ to ‘cancer cells’ and during the reprogramming of somatic cells to stem cells. We currently have studies underway (targeted and unbiased) to identify new players in the epigenetic regulation of melanoma progression and drug resistance to targeted therapies, as these processes remain poorly understood. We are also investigating the role of histone chaperone mutations in the context of pediatric tumor biology.