SOX2-Dependent Transcription in Clock Neurons Promotes the Robustness of the Central Circadian Pacemaker

Abstract

Summary: Clock neurons within the mammalian suprachiasmatic nuclei (SCN) encode circadian time using interlocked transcription-translation feedback loops (TTFLs) that drive rhythmic gene expression. However, the contributions of other transcription factors outside of the circadian TTFLs to the functionality of the SCN remain obscure. Here, we report that the stem and progenitor cell transcription factor, sex-determining region Y-box 2 (SOX2), is expressed in adult SCN neurons and positively regulates transcription of the core clock gene, Period2. Mice lacking SOX2 selectively in SCN neurons display imprecise, poorly consolidated behavioral rhythms that do not entrain efficiently to environmental light cycles and that are highly susceptible to constant light-induced arrhythmicity. RNA sequencing revealed that Sox2 deficiency alters the SCN transcriptome, reducing the expression of core clock genes and neuropeptide-receptor systems. By defining the transcriptional landscape within SCN neurons, SOX2 enables the generation of robust, entrainable circadian rhythms that accurately reflect environmental time. : SOX2 is a stem-cell-associated pluripotency transcription factor whose role in neuronal populations is undefined. Cheng et al. show that ablating SOX2 expression in SCN clock neurons severely disrupts circadian behavioral rhythms. SOX2 is a transcriptional activator of the Period2 gene, and its absence reduces neuropeptide signaling in the SCN. Keywords: circadian rhythms, suprachiasmatic nucleus, stem cell transcription factor, transcription, SOX2, PERIOD2, behavior, RNA sequencing