Dual-Approach Co-expression Analysis Framework (D-CAF) Enables Identification of Novel Circadian Regulation From Multi-Omic Timeseries Data.

The circadian clock is a central driver of many biological and behavioral processes, regulating the levels of many genes and proteins, termed clock controlled genes and proteins (CCGs/CCPs), to impart biological timing at the molecular level. While transcriptomic and proteomic data has been analyzed to find potential CCGs and CCPs, multi-omic modeling of circadian data, which has the potential to enhance the understanding of circadian control of biological timing, remains relatively rare due to several methodological hurdles. To address this gap, a Dual-approach Co-expression Analysis Framework (D-CAF) was created to perform perturbation-robust co-expression analysis on time-series measurements of both transcripts and proteins. Applying this D-CAF framework to previously gathered transcriptomic and proteomic data from mouse macrophages gathered over circadian time, we identified small, highly significant clusters of oscillating transcripts and proteins in the unweighted similarity matrices and larger, less significant clusters of of oscillating transcripts and proteins using the weighted similarity network. Functional enrichment analysis of these clusters identified novel immunological response pathways that appear to be under circadian control. Overall, our findings suggest that D-CAF is a tool that can be used by the circadian community to integrate multi-omic circadian data to improve our understanding of the mechanisms of circadian regulation of molecular processes.