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Timing and amount of sleep are controlled by a set of master regulators in the brain. Recently, a novel factor USF1 was discovered. In order to examine the mechanisms of USF transcription factors in sleep, we conducted a multiethnic GWAS of sleep traits (N>500,000). USF transcription factors associated with insomnia and timing of sleep. In addition, variants at USF binding sites explained up to 20% of SNP-based heritability in sleep traits. Furthermore, 28 sites at USF1 binding sites were both significant in sleep traits and showed allele specific DNase directly at the USF binding sites, including an allele specific expression at USF1 binding site near a key circadian pace maker PER1. We then validated these effects in model organisms. Usf1 knock-out mice showed lower activity in dark, frequent napping, extreme sleepiness and severe fragmentation of sleep. The sleep defects were compensated by increase in total sleep amount, which was specific for non-REM sleep. Similar sleep fragmentation was seen after neuron specific knock-down of usf in flies. These findings evidence that USF transcription factors are master regulators that shape sleep. The effects of USFs are likely conveyed through small cumulative effects on a number of key circadian downstream targets.
Dr. Hanna Ollila examines the genetic determinants of sleep. She is a postdoctoral fellow mentored by professor Jonathan Pritchard at the Department of Genetics and Biology at Stanford University and by Richa Saxena at the Center of Genomic Medicine at Harvard. Her research focuses on discovery of novel factors that modify natural sleep and connect sleep with metabolic diseases. Prior to her current position she examined the genetic basis of autoimmune sleep disorder narcolepsy with Dr. Emmanuel Mignot at the Department of Psychiatry and Behavioral Sciences at Stanford.