Katie Weihbrecht and Bing He will Present Their Research on April 17, 2014
Characterizing the NPHP10 Mouse
Nephronophthisis (NPHP) is a recessive kidney disorder that is the leading cause of early onset, end-stage renal failure. Localization to the ciliary-centrosomal complex of many proteins mutated in cystic kidney disease provided a coalescing mechanism for NPHP-related ciliopathies (NPHP-RC). Aside from renal failure and kidney cysts, the two other main phenotypes are retinal and cerebellar degeneration. One such disease with NPHP-RC phenotypes is Bardet-Biedl Syndrome (BBS), with cardinal phenotypes of retinal degeneration, renal abnormalities, obesity, polydactyl, and learning disabilities. An NPHP gene associated with BBS is serologically defined colon cancer antigen 8 (SDCCAG8), later defined as NPHP10. BBS patients with NPHP10 mutations exhibit retinal and renal abnormalities, obesity, and learning disabilities. An NPHP10 knockout (KO) mouse model has been generated using a Sleeping Beauty transposon insertion and these KO mice die shortly after birth. Current work focuses on characterizing the phenotypes of this mouse and determining if death is due to a gross morphological defect or a severe signaling pathway defect.
Global View of Enhancer-Promoter Interactome in Human Cells
Enhancer mapping has been greatly facilitated by various genomic marks associated with it. However, little is available in our toolbox to link enhancers with their target promoters, hampering mechanistic understanding of enhancer-promoter (EP) interaction. We develop and characterize multiple genomic features for distinguishing true EP pairs from non-interacting pairs. We integrate these features into a probabilistic predictor for EP interactions. Multiple validation experiments demonstrate a significant improvement over state-of-the-art approaches. Systematic analyses of EP interactions across eleven cell types reveal several global features of EP interactions: 1) about 60% of EP interactions are tissue-specific; 2) promoters controlled by multiple enhancers have higher tissue specificity but the regulating enhancers are less conserved; 3) cohesin plays a role in mediating tissue-specific EP interactions via chromatin looping in a CTCF independent manner. Our approach presents a systematic and effective strategy to decipher the mechanisms underlying EP communication.