Mammalian Circadian Clocks

Circadian clocks are molecular oscillators with ~24-hour periods that drive daily biological rhythms. Such clocks are found in all of the major branches of life, and they likely represent ancient timekeeping systems important for predicting daily environmental cycles on our rotating planet. In mammals, circadian clocks are present in most if not all cells. These distributed clocks control a myriad of processes, in aggregate creating coherent 24-hour programs of physiology and behavior.

A picture of how circadian clocks are built has emerged in the last two decades. The core mechanism is a transcriptional feedback loop, wherein the protein products of several clock genes build the molecular machinery to inhibit the transcription factor responsible for their own production. The molecular components of circadian clocks are conserved from insects to humans.

The Weitz lab uses molecular biology, biochemistry, genetics, and structural biology to investigate the timekeeping mechanism of the mammalian circadian clock. The focus of our efforts at present is to understand the circadian clock in terms of the integrated functions of its several multi-protein machines, recently characterized in our laboratory. This effort is principally based on the purification of endogenous circadian clock protein complexes from mouse tissues and their biochemical analysis and structural study by cryo-electron microscopy (cryo-EM).

Our initial studies along these lines (e.g., Aryal et al., Mol. Cell, 2017) provided the first basic structural characterization of native circadian clock machinery from a eukaryote. We have made progress in single-particle cryo-EM analysis of native circadian clock complexes purified from mouse tissues, and we are working to obtain high-resolution structures. A successful outcome would have a revolutionary impact on our understanding of biological timekeeping.