Heat Shock Factor 1 Governs Sleep-Wake Cycles Across Species.

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Heat Shock Factor 1 (HSF1) is a key regulator of cellular proteostasis.
• The role of HSF1 in sleep regulation has not been previously investigated.

Purpose of the Study:

• To explore the function of HSF1 in regulating sleep-wake cycles.
• To identify HSF1-dependent molecular mechanisms involved in sleep regulation.

Main Methods:

• Analysis of nuclear HSF1 levels in mouse brains during sleep-wake cycles.
• CUT&RUN and RNA-sequencing to identify HSF1-regulated genes.
• Generation and analysis of systemic and brain-specific Hsf1 knockout mice.
• Drosophila models to assess conserved HSF1 function in sleep.

Main Results:

• Nuclear HSF1 levels oscillate with sleep-wake states, increasing during wakefulness and decreasing during sleep.
• HSF1 regulates genes involved in synaptic organization, extending its known functions.
• Hsf1 knockout mice exhibit altered sleep homeostasis, including increased delta power and sleep gene upregulation, but struggle with sleep maintenance due to disrupted synaptic organization.
• Drosophila HSF1 ortholog knockout results in fragmented sleep, indicating a conserved role.

Conclusions:

• HSF1 plays a novel and conserved role in regulating sleep homeostasis and maintenance.
• HSF1 influences sleep through the regulation of synaptic organization.
• HSF1 represents a potential therapeutic target for sleep disorders.