Steroid hormone receptors through Cry2 are key players in the circadian clock response to serum

Circadian clocks are cell-autonomous oscillators that are present in most cells of the body and temporally coordinate their function. Alignment of cellular clocks with each other and the environment is mediated mostly through blood borne signals. Although serum is a potent resetting signal for circadian clocks, the underlying intracellular molecular underpinnings are largely unknown. Here, we employ Circa-SCOPE, a high-throughput single-cell method for constructing Phase Transition Curves (PTCs), to classify intracellular signaling pathways and clock-components that participate in clock resetting by serum. We identify steroid hormone, including sex-hormone receptors as key mediators of serum-induced phase resetting. Unexpectedly, we discover that Cry2 plays a central role in the response to serum and specifically to steroid hormones, irrespectively of its effect on the clock period-length. Furthermore, we find that PTCs are largely unaffected by the period-length. Overall, our findings provide important insight on intracellular determinant of the clock response to serum.