Mouse-human experimental epigenetic analysis unmasks dietary targets and genetic liability for diabetic phenotypes.

Using a functional approach to investigate the epigenetics of type 2 diabetes (T2D), we combine three lines of evidence-diet-induced epigenetic dysregulation in mouse, epigenetic conservation in humans, and T2D clinical risk evidence-to identify genes implicated in T2D pathogenesis through epigenetic mechanisms related to obesity. Beginning with dietary manipulation of genetically homogeneous mice, we identify differentially DNA-methylated genomic regions. We then replicate these results in adipose samples from lean and obese patients pre- and post-Roux-en-Y gastric bypass, identifying regions where both the location and direction of methylation change are conserved.

Modeling the clinical phenotype of BTK inhibition in the mature murine immune system.

Inhibitors of Bruton's tyrosine kinase (BTK) possess much promise for the treatment of oncologic and autoimmune indications. However, our current knowledge of the role of BTK in immune competence has been gathered in the context of genetic inactivation of btk in both mice and man. Using the novel BTK inhibitor PF-303, we model the clinical phenotype of BTK inhibition by systematically examining the impact of PF-303 on the mature immune system in mice.

CACN-1/Cactin interacts genetically with MIG-2 GTPase signaling to control distal tip cell migration in C. elegans.

The two specialized C. elegans distal tip cells (DTCs) provide an in vivo model system for the study of developmentally regulated cell migration. We identified cacn-1/cactin, a well-conserved, novel regulator of cell migration in a genome-wide RNAi screen for regulators of DTC migration.