Summary/Abstract Environmental-Circadian Disruption such as shiftwork and Jetlag imposes major risk on human health in the U.S. and abroad. It increases the risk of many metabolic and cardiovascular disorders and cancers and effects over 16% of the U.S. workforce. Yet, the molecular underpinnings of this process remain unclear. In a proteomic analysis of proteins interacting with Cry1, we identified 10 components of COMPASS complexes. These enzymatic complexes regulate gene transcription by catalyzing the addition of methyl groups to lysine 4 of histone 3 (H3K4mes) of local chromatin. Interestingly, these chromatin marks respond to environmental circadian entrainment information such as light, temperature or nutrients. They also happen in a circadian rhythmic manner and modulate DNA methylation, a determinant of gene transcription and disease development. Furthermore, functional perturbations of various COMPASS components were also implicated in pathological conditions associated with disharmony of environmental and circadian cycles such as breast cancer and obesity. We thus hypothesize that COMPASS complexes play a key role in environmental-circadian alignment. Under environmental-circadian alignment condition, COMPASS complexes are recruited by Cry1 to rhythmically methylate local H3K4s, which prevent recruitment of DNA methyltransferases resulting in perturbations of DNA methylation and expression of core clock gene(s). This methylation cascade modulates the circadian pattern of gene expression, ensuring alignment of the circadian system with daily environmental cycles. The methylation cascade fails to initiate when internal circadian system mis-aligns with external environmental cycles, leading to perturbation of the homeostatic state of cells and development of disorders. We will investigate this hypothesis by pursuing the following initial aims: 1: To characterize circadian Cry1::COMPASS interaction; Aim 2: To investigate the role of COMPASS complexes in methylation of core clock genes; Aim 3: To study the effects of environmental- circadian disruption on COMPASS function. The results of this project might unveil the molecular mechanism of a fundamental biological process: synchronization of daily internal physiological rhythms with external environmental cycles. They might also illuminate the nuts and bolts of disorders associated with shiftwork.