Functional genomics approaches are becoming very powerful strategies to identify novel transcriptional signaling pathways in complex regulatory processes such as cell differentiation and cancer development. Food intake is associated with hepatic transcriptional reprogramming regulated by multiple transcription factors. In the past these processes have mostly been described by relative simple gene-by-gene approaches. We propose to use genome-wide technologies such as DNase-seq, ChIP-seq and RNA-seq to comprehensive identify differentially regulated hepatic transcriptional networks in response to acute feeding in chow fed and corresponding diet induced obese mouse models. Importantly, we will complement with SILAC based quantitative mass spectrometry to identify novel transcriptional co-regulators controlling the transcriptional networks differentially regulated by the feeding regimens. This will identify feeding controlled transcriptional co-regulators potentially deregulated in obesity. We have preliminary DNAse-seq data from the chow fed mouse model that suggests attenuated activity of several transcription factors including GR, C/EBP, FOXO, CREB and PPAR in response to acute feeding. Interestingly, GSK3beta a downstream target of the insulin/PI3K-signaling pathway regulates most of these transcription factors and GSK3beta deregulation is associated with dysfunctional glucose homeostasis and onset of diabetes. We hypothesize that GSK3beta function as a transcriptional co-regulator for many of these transcription factors and insulin attenuates activity of these factors through insulin inhibition of GSK3beta occupancy of chromatin. Importantly, GSK3beta occupancy of chromatin has so far not been demonstrated and GSK3beta targeting chromatin may have widespread functional implication of hepatic transcriptional signaling, glucose homeostasis and development of diet-induced obesity.
|Effective start/end date||01/03/2015 → 31/08/2017|