Network Regulation of Rhythmic Transcription in Neurospora crassa

Abstract

Roughly half of eukaryotic mRNAs cycle in abundance under control of the circadian clock, with some mRNAs peaking in levels during the day, and other mRNAs peaking in levels during the night. While phase regulation is critical to maintain internal temporal order and an organism’s physical and mental health, how rhythmic phase is generated and controlled was not known. In this dissertation, I discovered that rhythmic phase regulation in the model organism Neurospora crassa is controlled through at least 14 clock-regulated transcription factors (TF) that form a network composed of feed-forward and feed-back loops. I show that the loss of one of the network TFs, ADV-1, globally impacts the phase of its target clock-controlled genes (ccgs) involved in amino acid and fatty acid metabolism. Furthermore, two TFs within the network, CSP-1 and CSP-2 were found to be required for ADV-1 phase control, and a feed-forward loop motif involving CSP-1 and CLR-1 was shown to be necessary and sufficient for controlling ADV-1 phase. However, single deletions of most of the TFs in the network had no effect on ADV-1 rhythms, indicating that there is redundancy in the network. Together, these data demonstrate a role for a circadian TF network in rhythmic phase control and support the idea that the network provides redundancy to filter noise to respond appropriately to phase-shifting cues.