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Cited by 41Circadian rhythm and melatoninSleep and Wakefulness ResearchNeuropeptides and Animal Physiology

An LHX1-Regulated Transcriptional Network Controls Sleep/Wake Coupling and Thermal Resistance of the Central Circadian Clockworks

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Bedont, Joseph L., LeGates, Tara A., Buhr, Ethan, Bathini, Abhijith, Ling, Jonathan P., Bell, Benjamin, Wu, Mark N., Wong, Philip C. +4 more·2017·Current Biology
DOI 10.1016/j.cub.2016.11.008PMC PMC5269403
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Abstract

The suprachiasmatic nucleus (SCN) is the central circadian clock in mammals. It is entrained by light but resistant to temperature shifts that entrain peripheral clocks [1-5]. The SCN expresses many functionally important neuropeptides, including vasoactive intestinal peptide (VIP), which drives light entrainment, synchrony, and amplitude of SCN cellular clocks and organizes circadian behavior [5-16]. The transcription factor LHX1 drives SCN Vip expression, and cellular desynchrony in Lhx1-deficient SCN largely results from Vip loss [17, 18]. LHX1 regulates many genes other than Vip, yet activity rhythms in Lhx1-deficient mice are similar to Vip-/- mice under light-dark cycles and only somewhat worse in constant conditions. We suspected that LHX1 targets other than Vip have circadian functions overlooked in previous studies. In this study, we compared circadian sleep and temperature rhythms of Lhx1- and Vip-deficient mice and found loss of acute light control of sleep in Lhx1 but not Vip mutants. We also found loss of circadian resistance to fever in Lhx1 but not Vip mice, which was partially recapitulated by heat application to cultured Lhx1-deficient SCN. Having identified VIP-independent functions of LHX1, we mapped the VIP-independent transcriptional network downstream of LHX1 and a largely separable VIP-dependent transcriptional network. The VIP-independent network does not affect core clock amplitude and synchrony, unlike the VIP-dependent network. These studies identify Lhx1 as the first gene required for temperature resistance of the SCN clockworks and demonstrate that acute light control of sleep is routed through the SCN and its immediate output regions.

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  • These exposures have been associated with coordinated alterations in stress-response regulation, circadian and sleep-related pathways, and metabolic processes.

    “These exposures have been associated with coordinated alterations in stress-response regulation, circadian and sleep-related pathways, and metabolic processes (102–115).”

    From Epigenetic changes associated with multi-generational trauma: characterization, mechanisms, and therapeutics (2026) · cites this paper as [111]

    The Results and Discussion section on sleep/wake reports disrupted circadian and light control of sleep in Lhx1-deficient mice; the section on temperature resistance reports altered circadian rhythms after LPS-induced fever. These passages support the circadian and sleep-related portion, but do not establish coordinated alterations in stress-response regulation and metabolic processes associated with the unspecified exposures. No page numbers are available in our copy. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • These changes have been associated with variation in memory processing, sleep duration, and circadian rhythm regulation, as well as differences in PTSD symptom severity.

    “These changes have been associated with variation in memory processing, sleep duration, and circadian rhythm regulation, as well as differences in PTSD symptom severity (103, 109–111).”

    From Epigenetic changes associated with multi-generational trauma: characterization, mechanisms, and therapeutics (2026) · cites this paper as [111]

    The Results and Discussion section on light and circadian control of sleep/wake reports altered sleep timing and disrupted circadian regulation in Lhx1-deficient mice. It says total time in each sleep/wake state over 24 hours was unchanged; the paper does not address memory processing or PTSD symptom severity. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Differential methylation of sleep and circadian genes such as PAX8 and LHX1 has been reported in veterans with PTSD.

    “Differential methylation of sleep and circadian genes such as PAX8 and LHX1 has been reported in veterans with PTSD (103, 109–111).”

    From Epigenetic changes associated with multi-generational trauma: characterization, mechanisms, and therapeutics (2026) · cites this paper as [111]

    The Results and Discussion section on LHX1 transcriptional networks describes circadian regulation in mouse suprachiasmatic nuclei, not differential methylation in veterans with PTSD. Searches for PAX8, PTSD, veterans, and methylation found no passage in our copy reporting the attributed finding. (LLM, conf=0.76)

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Authors
Bedont, J. L., LeGates, T. A., Buhr, E., Bathini, A., Ling, J. P., Bell, B., Wu, M. N., Wong, P. C., Van Gelder, R. N., Mongrain, V., Hattar, S., & Blackshaw, S.
Affiliations
  • Johns Hopkins University (US)
  • University of Washington (US)
Corresponding author
  • Hattar, Samer
  • Blackshaw, Seth
ORCID
Venue
Current Biology
Publisher
Elsevier BV
Published
2017-01
Volume
27
Issue
1
Pages
128-136
ISSN
0960-9822 (ISSN-L)
DOI
10.1016/j.cub.2016.11.008
PMC
PMC5269403
OpenAlex
W2563950915
Cited by
41
References
2
Citations by year
2026: 1 · 2025: 6 · 2024: 9 · 2023: 2 · 2022: 2 · 2021: 1 · 2020: 8 · 2019: 7 · 2018: 5
FWCI
2.54
Type
journal article
Language
en
Open access
Licence
Locations
  • Current Biology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Johns Hopkins Brain Science Institute
  • Wilmer Eye Institute Visual Neuroscience Training Program
  • National Science Foundation Graduate Research Fellowship Program
  • Fonds de Recherche du Québec-Santé (22210, 30831)
  • Canadian Institutes of Health Research (340196-126252)
  • NIH (EY001730)
  • Research to Prevent Blindness
Topics
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Sleep and Wakefulness Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
Keywords
Lhx1, suprachiasmatic nucleus, circadian clock, vasoactive intestinal peptide, sleep-wake cycle, light entrainment, temperature entrainment, transcriptional regulatory networks
MeSH terms
Animals, Circadian Rhythm, Gene Expression Regulation, Hot Temperature, Male, Mice, Inbred C57BL, Sleep, Suprachiasmatic Nucleus, Transcription Factors, Vasoactive Intestinal Peptide, Wakefulness, Signal Transduction, Photoperiod, Mice, Knockout, Mice, Gene Regulatory Networks, Circadian Clocks, High-Throughput Nucleotide Sequencing, LIM-Homeodomain Proteins

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