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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE283586 | GEO | 2025/12/05

REPOSITORIES: GEO

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

Project description: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.

2025-12-05 | GSE283582 | GEO

Heat Shock Factor 1 Governs Sleep-Wake Cycles Across Species [CUT&RUN]

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Sivery2016 - A mammalian heat shock response model

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2022-01-25 | MODEL2201210001 | BioModels

Genetic and Epigenetic Determinants Establish a Continuum of Hsf1 Occupancy and Activity Across the Yeast Genome

Project description:We performed ChIP-seq of Hsf1 under non heat shock, 5-minute heat shock and 120 minute heat shock conditions. We used the conditional chemical genetics approach known as “anchor away” (AA) to rapidly inactivate Hsf1. We coupled Hsf1-AA to and nascent RNA seq (NAC)-seq to define the genes whose expression depends on Hsf1 during heat shock.

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Project description:Disrupted circadian rhythmicity is a prominent feature of modern society and has been designated as a probable carcinogen by the World Health Organization. However, the biological mechanisms that connect circadian disruption and cancer risk remain largely undefined. We demonstrate that exposure to chronic circadian disruption (chronic jetlag, CJL) increases tumor formation in a mouse model of KRAS-driven lung cancer. Molecular characterization of tumors and tumor-bearing lung tissues revealed that CJL enhances the expression of heat shock factor 1 (HSF1) target genes. Consistently, exposure to CJL disrupted the highly rhythmic nuclear trafficking of HSF1 in the lung, resulting in an enhanced accumulation of HSF1 in the nucleus. HSF1 has been shown to promote tumorigenesis in other systems, and we find that pharmacological inhibition of HSF1 reduces the growth of KRAS-mutant human lung cancer cells. These findings implicate HSF1 as a molecular link between circadian disruption and enhanced tumorigenesis.

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HSF1 mediated Gene regulation in T cells at normal (37C) and febrile (40C) temperatures

Project description:HSF1 is a major transcriptional regulator of heat shock responses. Many cells activate HSF1 in response to heat shock temperatures (>42oC) and other cellular stress causing agents. Unlike other cell types, T cells activate HSF1 in response to T cell activation or when exposed to febrile (40oC) temperatures, suggesting a role for HSF1 beyond the heat-shock response. We used microarray analysis and HSF1 knock-out mice to study the HSF1 mediated gene regulation in activated T cells under normal and fever temperatures.

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Transriptional profiling upon heat shock and recovery in cells deficient for FBXW7 and their wild type counterpart.

Project description:FBXW7 modulates stress response by post-translational modification of HSF1 HSF1 orchestrates the heat-shock response upon exposure to heat stress and activates a transcriptional program vital for cancer cells. Genes positively regulated by HSF1 show increeased expression during heat shock while their expression is reduced during recovery. Genes negatively regulated by HSF1 show the opposite pattern. In this study we utilized the HCT116 FBXW7 KO colon cell line and its wild type counterpart to monitor gene expression changes during heat shock (42oC, 1 hour) and recovery (37oC for 2 hours post heat shock) using RNA sequencing. These results revealed that the heat-shock response pathway is prolonged in cells deficient for FBXW7.

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Sleep-wake cycles drive daily dynamics of synaptic phosphorylation

Project description:The circadian clock drives daily changes of physiology, including sleep-wake cycles, by regulating transcription, protein abundance and function. Circadian phosphorylation controls cellular processes in peripheral organs, but little is known about its role in brain function and synaptic activity. We applied advanced quantitative phosphoproteomics to mouse forebrain synaptoneurosomes isolated across 24h, accurately quantifying almost 8,000 phosphopeptides. Remarkably, half of the synaptic phosphoproteins, including numerous kinases, had large-amplitude rhythms peaking at rest-activity and activity-rest transitions. Bioinformatic analyses revealed global temporal control of synaptic function via phosphorylation, including synaptic transmission, cytoskeleton reorganization and excitatory/inhibitory balance. Remarkably, sleep deprivation abolished 98% of all phosphorylation cycles in synaptoneurosomes, indicating that sleep-wake cycles rather than circadian signals are main drivers of synaptic phosphorylation, responding to both sleep and wake pressures.

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Genome-wide HSF1 binding sites in control and heat shocked spermatocytes and hepatocytes

Project description:In somatic cells elevated temperature induces activation of the heat shock transcription factor 1 (HSF1) what leads to heat shock proteins synthesis and cytoprotection. However, in the male germ cells (spermatocytes) upon HSF1 activation, caspase-3 dependent apoptosis is induced and spermatogenic cells are actively eliminated. To find out molecular targets of HSF1 in all promoter regions, and to elucidate a mechanism of such diverse HSF1 activity we carried out genome-wide HSF1 binding analysis in control and heat-shocked cells, either spermatogenic or somatic. As model somatic cells we used hepatocytes that respond to hyperthermia in a classical way by induction of heat shock genes transcription. As spermatogenic cells we used a fraction of cells enriched with spermatocytes, which are the most sensitive to damage in elevated temperatures. Using isolated spermatocytes we avoided the influence of the somatic testicular component on the our final results.

2012-08-28 | GSE40390 | GEO

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