Heat Shock Factor 1 Governs Sleep-Wake Cycles Across Species [snRNA-Seq]

Sleep represents a fundamental biological necessity, yet the molecular mechanisms controlling this essential process remain largely unknown. Sleep disruption marks numerous pathological states, suggesting undiscovered molecular regulators govern this vital function. While studies have mapped gene expression during sleep, the master regulators that translate sleep pressure into sleep behavior have remained elusive. We demonstrate that Heat Shock Factor 1 (HSF1), previously characterized solely as a stress response transcription factor, serves as a critical molecular switch enabling sleep. HSF1's nuclear levels oscillate with sleep-wake cycles in mouse cortex and increase markedly during sleep deprivation. Systemic and brain-specific Hsf1 knockout mice display sleep disruption due to synaptic dysregulation, even as they accumulate normal sleep pressure. Nuclear HSF1 orchestrates a novel transcriptional program controlling synaptic organization, distinct from its canonical heat shock response. Single-nucleus RNA sequencing reveals that HSF1 deficiency triggers widespread dysregulation of synaptic genes across neuronal and glial populations. This mechanism shows evolutionary conservation, as Drosophila lacking the HSF1 ortholog display similar sleep phenotypes despite elevated sleep pressure. Our findings uncover an unexpected role for this classical stress factor and establish HSF1 as a molecular bridge linking sleep pressure to sleep behavior. These results suggest new therapeutic approaches for sleep disorders. Overall design: To investigate the functions of HSF1 in sleep regulation, we established conditional Hsf1 knockout mouse model and analyzed the transcriptional alterations in control and the knockout mouse brain under normal sleep and sleep deprived conditions using single nucleus RNA sequencing (snRNA-seq).