Current Research Projects
Current interests include:
- Assigning function to disease mutations or susceptibility alleles for metabolic and cardiovascular disease.
- Dissecting the role of epigenetic modifications during cardiac differentiation.
- Developing novel ways to phenotype human subjects or human cells, such as cell-based or imaging phenotypes.
Our group works closely with several programs and investigators at the Broad Institute of Harvard and Massachusetts Institute of Technology, as well as at Massachusetts General Hospital.
Assigning function to disease mutations or susceptibility alleles for metabolic and cardiovascular disease.
As validated susceptibility alleles are discovered for cardiovascular and metabolic diseases, the next important challenge is to assign biological function to these alleles. However, this has proven challenging, in part because many susceptibility alleles do not lend themselves to study by traditional methods; they may fall within non-coding DNA, for instance, or many different SNPs over large distances may contribute to disease susceptibility.
Genetic interaction screens (analogous to those performed in model organisms such as yeast or C. elegans) can identify pathways that functionally interact with disease mutations and thereby help assign function to these alleles. As an example of this approach, we have studied lymphoblast cell lines from individuals with MODY 1, a monogenic form of type 2 diabetes caused by mutation in the orphan nuclear receptor HNF4α. Patient-derived lymphoblast lines that are mutant or wild-type at HNF4α are treated with thousands of small molecules of known effect (including hundreds of FDA-approved drugs), and their effects are assessed using high-throughput assays of cellular metabolism. The data are analyzed to identify groups of small molecules that induce distinct effects in mutant vs. wild-type cells, suggesting that the small molecules, or their protein targets, functionally interact with HNF4α. We complement this approach with genome-wide studies of gene expression in mutant vs. wild-type cells. This two-pronged analysis has identified both expected and novel synthetic interactions with HNF4α. We plan to extend this work to validated susceptibility alleles for complex diseases, using either cell lines or primary isolates.
Dissecting the role of histone modifications in cardiac differentiation using novel small molecule libraries.
Dynamic changes in histone acetylation and methylation contribute to normal cardiac development, as well as to the cardiac hypertrophic response to physiologic stress. A host of histone-modifying enzymes potentially participate in this process (e.g., histone acetyl transferases, histone deacetylases, histone methyl transferases, histone demethylases), but existing studies have largely studied these enzymes one at a time.
We have undertaken an approach that uses novel synthetic small molecule libraries that are biased to modulate histone-modifying enzymes. We screen these libraries for their ability to induce cardiac differentiation using high-throughput automated microscopy, and have identified several compounds that can induce a cardiac phenotype in murine embryonal carcinoma cells as well as in human ES cells. Current studies use these novel molecules as probes to illuminate the role of different histone modifications in cardiac differentiation, and may also provide a rationale for epigenetic modulation as an adjunct to regenerative therapies for the heart.