Complex metabolic diseases such as cancer, diabetes and obesity result from the interaction of multiple genetic and environmental factors. We are exploring the interaction of epigenetic and genetic variation in the development of complex disease. We utilize an integrative approach combining computational and experimental approaches to study these problems. Genome-wide profiles of transcription factor binding, chromatin modifications, gene expression and genetic variation all provide one-dimensional views of genome regulation. To truly understand the regulatory networks involved in normal development – and how these networks are disrupted in disease – we must integrate these data sets.
We recently reported that one manner by which environmental factors can alter molecular pathways is through modifications to chromatin. We demonstrated that high fat diet leads to chromatin remodeling in the liver of mice and that this chromatin remodeling occurs mostly at liver regulatory regions. We furthermore showed that the regions of greatest diet-induced remodeling are strain dependent, indicating a role for genetic factors to influence this response. We are now expanding this study by using a large panel of genetically distinct strains that show phenotypic diversity in terms of metabolic disease. We have characterized several genomic loci that are unique to strains that are resistant to metabolic disease and we are investigating the effect of manipulation of these loci on development of metabolic disease. We believe this represents an attractive pathway to novel therapeutics. We are additionally investigating the potential persistence of diet-induced chromatin remodeling upon the removal of high fat diet. This is important because many individuals who develop metabolic diseases have susceptibility to metabolic complications later in life, even if they are able to mitigate disease progression through lifestyle changes.
Another area of interest is in the establishment of chromatin domains in development and how disruption of these domains leads to disease progression. We have demonstrated that repressive heterochromatin domains are established at specific genomic loci at certain stages of hematopoietic stem cell differentiation and that this chromatin modification leads to altered chromatin environment. We have furthermore been investigating how environmental factors to disrupt chromatin domains and the potential for these alterations to contribute to disease.
Beisi Xu, Ph.D.
626-256-4673, ext. 63300
626-256-4673 ext. 64521
Candi Trac, M.S.
Research Associate II
626-256-4673, ext. 64521