Circadian clock regulation by compartmentalized protein translation

Cells exquisitely compartmentalize many biochemical reactions through phase-separated membrane-less organelles. Besides spatial organization, many biological processes are temporally regulated. While both transcription and translation oscillate in a rhythmic manner, the regulatory mechanism of the latter is understudied. Here we report that the translational regulation during circadian cycles is associated with oscillating phase separation controlled by Ataxin-2 and Ataxin-2L. Ataxin-2/2L forms rhythmic condensates through phase separation in the mammalian central clock suprachiasmatic nucleus to selectively concentrate the transcripts of the core clock genes and recruit the mRNA translation machinery. The rhythmic translational activation is abolished in cells and mouse circadian behavior is altered in the absence of Ataxin-2/2L. During aging or neurodegeneration, Ataxin-2/2L form large, irreversible puncta that no longer regulate translation. Overall, our results unveil Ataxin-2/2L's role as the master regulators of rhythmic translation via a oscillating phase-separation, and explained the reason for their dysfunction in disease states. Overall design: Ribosome profiling of U2OS WT, Ataxin-2 KO, Ataxin-2L KO and DKO cells at 4 hours and 12 hours after synchronization with DXMS.