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

Joseph L. Bedont, Tara A. LeGates, Ethan Buhr, Abhijith Bathini, Jonathan P. Ling, Benjamin Bell, Mark N. Wu, Philip C. Wong, Russell N. Van Gelder, Valerie Mongrain, Samer Hattar, Seth Blackshaw

Research output: Contribution to journalArticle

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.

LanguageEnglish (US)
Pages128-136
Number of pages9
JournalCurrent Biology
Volume27
Issue number1
DOIs
StatePublished - Jan 9 2017

Fingerprint

vasoactive intestinal peptide
Suprachiasmatic Nucleus
Gene Regulatory Networks
Vasoactive Intestinal Peptide
sleep
Heat resistance
Sleep
Hot Temperature
heat
Clocks
mice
Light
Circadian Clocks
Genes
Temperature
temperature
Mammals
neuropeptides
Neuropeptides
circadian rhythm

Keywords

  • circadian
  • LHX1
  • light
  • LPS
  • resistance
  • SCN
  • sleep
  • temperature
  • transcriptome
  • VIP

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

An LHX1-Regulated Transcriptional Network Controls Sleep/Wake Coupling and Thermal Resistance of the Central Circadian Clockworks. / Bedont, Joseph L.; LeGates, Tara A.; Buhr, Ethan; Bathini, Abhijith; Ling, Jonathan P.; Bell, Benjamin; Wu, Mark N.; Wong, Philip C.; Van Gelder, Russell N.; Mongrain, Valerie; Hattar, Samer; Blackshaw, Seth.

In: Current Biology, Vol. 27, No. 1, 09.01.2017, p. 128-136.

Research output: Contribution to journalArticle

Bedont, JL, LeGates, TA, Buhr, E, Bathini, A, Ling, JP, Bell, B, Wu, MN, Wong, PC, Van Gelder, RN, Mongrain, V, Hattar, S & Blackshaw, S 2017, 'An LHX1-Regulated Transcriptional Network Controls Sleep/Wake Coupling and Thermal Resistance of the Central Circadian Clockworks' Current Biology, vol 27, no. 1, pp. 128-136. DOI: 10.1016/j.cub.2016.11.008
Bedont JL, LeGates TA, Buhr E, Bathini A, Ling JP, Bell B et al. An LHX1-Regulated Transcriptional Network Controls Sleep/Wake Coupling and Thermal Resistance of the Central Circadian Clockworks. Current Biology. 2017 Jan 9;27(1):128-136. Available from, DOI: 10.1016/j.cub.2016.11.008
Bedont, Joseph L. ; LeGates, Tara A. ; Buhr, Ethan ; Bathini, Abhijith ; Ling, Jonathan P. ; Bell, Benjamin ; Wu, Mark N. ; Wong, Philip C. ; Van Gelder, Russell N. ; Mongrain, Valerie ; Hattar, Samer ; Blackshaw, Seth. / An LHX1-Regulated Transcriptional Network Controls Sleep/Wake Coupling and Thermal Resistance of the Central Circadian Clockworks. In: Current Biology. 2017 ; Vol. 27, No. 1. pp. 128-136
@article{38fd1aa753ff4f01ac5e8af20dbc3ff2,
title = "An LHX1-Regulated Transcriptional Network Controls Sleep/Wake Coupling and Thermal Resistance of the Central Circadian Clockworks",
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.",
keywords = "circadian, LHX1, light, LPS, resistance, SCN, sleep, temperature, transcriptome, VIP",
author = "Bedont, {Joseph L.} and LeGates, {Tara A.} and Ethan Buhr and Abhijith Bathini and Ling, {Jonathan P.} and Benjamin Bell and Wu, {Mark N.} and Wong, {Philip C.} and {Van Gelder}, {Russell N.} and Valerie Mongrain and Samer Hattar and Seth Blackshaw",
year = "2017",
month = "1",
day = "9",
doi = "10.1016/j.cub.2016.11.008",
language = "English (US)",
volume = "27",
pages = "128--136",
journal = "Current Biology",
issn = "0960-9822",
publisher = "Cell Press",
number = "1",

}

TY - JOUR

T1 - An LHX1-Regulated Transcriptional Network Controls Sleep/Wake Coupling and Thermal Resistance of the Central Circadian Clockworks

AU - Bedont,Joseph L.

AU - LeGates,Tara A.

AU - Buhr,Ethan

AU - Bathini,Abhijith

AU - Ling,Jonathan P.

AU - Bell,Benjamin

AU - Wu,Mark N.

AU - Wong,Philip C.

AU - Van Gelder,Russell N.

AU - Mongrain,Valerie

AU - Hattar,Samer

AU - Blackshaw,Seth

PY - 2017/1/9

Y1 - 2017/1/9

N2 - 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.

AB - 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.

KW - circadian

KW - LHX1

KW - light

KW - LPS

KW - resistance

KW - SCN

KW - sleep

KW - temperature

KW - transcriptome

KW - VIP

UR - http://www.scopus.com/inward/record.url?scp=85009141794&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85009141794&partnerID=8YFLogxK

U2 - 10.1016/j.cub.2016.11.008

DO - 10.1016/j.cub.2016.11.008

M3 - Article

VL - 27

SP - 128

EP - 136

JO - Current Biology

T2 - Current Biology

JF - Current Biology

SN - 0960-9822

IS - 1

ER -