Supplement - Molecular Clock Regulation of b-cell Gene Networks in T1DM

Type 1 diabetes mellitus is triggered by autoimmune destruction of mature pancreatic beta-cells however growing evidence indicates that factors involved in beta-cell growth, proliferation and stress response modulate the onset, progression, and magnitude of beta-cell destruction through mechanisms that are not fully understood. Recent studies in our group and others have uncovered a central role of the endogenous circadian transcription network in beta-cell function, proliferation, and in inflammation, pointing towards a novel pathway in the regulation of islet survival and insulin production (Science, 2009, Nature, 2010 and 2012). At the molecular level, the clock is encoded by a set of transcriptional activators (CLOCK/BMAL1) that induce the expression of repressors (CRY/PER) that feedback to inhibit their activity forming a transcription-translation feedback loop that oscillates with a 24-hour periodicity in both hypothalamic pacemaker cells and peripheral beta-cells. Clocks synchronize cell cycle and replication with the 24-hour light-dark cycle and mounting evidence indicates that they play a role in tissue regeneration and proliferation, while we have shown that clock disruption isolated to the beta-cell causes hypoinsulinemia and diabetes mellitus. The overarching aims of this 1 year innovation application seek to establish a genomic understanding of the circadian gene regulatory network within the beta-cell of human islets through the dual analysis of CLOCK/BMAL1 genome occupancy by chromatin immunoprecipitation and by RNA sequencing.