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

doi:10.1016/j.cub.2016.11.008

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 journal › Article › peer-review

17 Scopus citations

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.

Original language	English (US)
Pages (from-to)	128-136
Number of pages	9
Journal	Current Biology
Volume	27
Issue number	1
DOIs	https://doi.org/10.1016/j.cub.2016.11.008
State	Published - Jan 9 2017

Keywords

LHX1
LPS
SCN
VIP
circadian
light
resistance
sleep
temperature
transcriptome

ASJC Scopus subject areas

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

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10.1016/j.cub.2016.11.008

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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. (2017). An LHX1-Regulated Transcriptional Network Controls Sleep/Wake Coupling and Thermal Resistance of the Central Circadian Clockworks. Current Biology, 27(1), 128-136. https://doi.org/10.1016/j.cub.2016.11.008

@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 = "LHX1, LPS, SCN, VIP, circadian, light, resistance, sleep, temperature, transcriptome",

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",

note = "Funding Information: We thank the Johns Hopkins Deep Sequencing and Microarray Core for library prep and sequencing; Hong Wang for genotyping; Shirley Zhang and Ga{\'e}tan Poirier for help with analysis; and Amita Sehgal and Wendy Yap for comments. This work was supported by Johns Hopkins Brain Science Institute. J.L.B. was supported by Wilmer Eye Institute Visual Neuroscience Training Program (VNTP) and National Science Foundation Graduate Research Fellowship Program (NSF GRFP) fellowships. V.M. is supported by the Fonds de Recherche du Qu{\'e}bec-Sant{\'e} (22210 and 30831) and Canadian Institutes of Health Research (340196-126252). E.B. and R.V.G. were supported by NIH grant EY001730 and an unrestricted grant from Research to Prevent Blindness. S.B. was a W.M. Keck Distinguished Young Scholar in Medical Research. Publisher Copyright: {\textcopyright} 2017 Elsevier Ltd",

year = "2017",

month = jan,

day = "9",

doi = "10.1016/j.cub.2016.11.008",

language = "English (US)",

volume = "27",

pages = "128--136",

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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

N1 - Funding Information: We thank the Johns Hopkins Deep Sequencing and Microarray Core for library prep and sequencing; Hong Wang for genotyping; Shirley Zhang and Gaétan Poirier for help with analysis; and Amita Sehgal and Wendy Yap for comments. This work was supported by Johns Hopkins Brain Science Institute. J.L.B. was supported by Wilmer Eye Institute Visual Neuroscience Training Program (VNTP) and National Science Foundation Graduate Research Fellowship Program (NSF GRFP) fellowships. V.M. is supported by the Fonds de Recherche du Québec-Santé (22210 and 30831) and Canadian Institutes of Health Research (340196-126252). E.B. and R.V.G. were supported by NIH grant EY001730 and an unrestricted grant from Research to Prevent Blindness. S.B. was a W.M. Keck Distinguished Young Scholar in Medical Research. Publisher Copyright: © 2017 Elsevier Ltd

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 - LHX1

KW - LPS

KW - SCN

KW - VIP

KW - circadian

KW - light

KW - resistance

KW - sleep

KW - temperature

KW - transcriptome

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M3 - Article

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AN - SCOPUS:85009141794

SN - 0960-9822

VL - 27

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JO - Current Biology

JF - Current Biology

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ER -

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

Abstract

Keywords

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