Cell-specific regulation of the circadian clock by BMAL1 in the paraventricular nucleus: Implications for regulation of systemic biological rhythms

Circadian rhythms are internal biological rhythms driving temporal tissue-specific, metabolic programs. Loss of the circadian transcription factor BMAL1 in the paraventricular nucleus (PVN) of the hypothalamus reveals its importance in metabolic rhythms, but its functions in individual PVN cells are...

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Published in:	Cell reports (Cambridge) Vol. 43; no. 7; p. 114380
Main Authors:	Van Drunen, Rachel, Dai, Yulin, Wei, Haichao, Fekry, Baharan, Noori, Sina, Shivshankar, Samay, Bravo, Rafael, Zhao, Zhongming, Yoo, Seung-hee, Justice, Nicholas, Wu, Jia Qian, Tong, Qingchun, Eckel-Mahan, Kristin
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 23-07-2024 Elsevier
Subjects:	Animals ARNTL Transcription Factors - genetics ARNTL Transcription Factors - metabolism Astrocytes - metabolism BMAL1 ChIP-seq circadian Circadian Clocks - genetics Circadian Rhythm - physiology CP: Neuroscience Gene Expression Regulation Male metabolism Mice Mice, Inbred C57BL Mice, Knockout Neurons - metabolism Oligodendroglia - metabolism oxytocin Oxytocin - metabolism Paraventricular Hypothalamic Nucleus - metabolism paraventricular nucleus (PVN) snRNA-seq circadian oxytocin CP: Neuroscience paraventricular nucleus (PVN) ChIP-seq metabolism BMAL1 snRNA-seq
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Summary:	Circadian rhythms are internal biological rhythms driving temporal tissue-specific, metabolic programs. Loss of the circadian transcription factor BMAL1 in the paraventricular nucleus (PVN) of the hypothalamus reveals its importance in metabolic rhythms, but its functions in individual PVN cells are poorly understood. Here, loss of BMAL1 in the PVN results in arrhythmicity of processes controlling energy balance and alters peripheral diurnal gene expression. BMAL1 chromatin immunoprecipitation sequencing (ChIP-seq) and single-nucleus RNA sequencing (snRNA-seq) reveal its temporal regulation of target genes, including oxytocin (OXT), and restoring circulating OXT peaks in BMAL1-PVN knockout (KO) mice rescues absent activity rhythms. While glutamatergic neurons undergo day/night changes in expression of genes involved in cell morphogenesis, astrocytes and oligodendrocytes show gene expression changes in cytoskeletal organization and oxidative phosphorylation. Collectively, our findings show diurnal gene regulation in neuronal and non-neuronal PVN cells and that BMAL1 contributes to diurnal OXT secretion, which is important for systemic diurnal rhythms. [Display omitted] •Loss of BMAL1 in the PVN leads to arrhythmic energy intake and energy expenditure•TRF improves rhythmicity in BMAL1-PVN KO mice•BMAL1 binds PVN target genes, driving highly diurnal and cell-specific gene expression•Diurnal OXT secretion is driven by PVN BMAL1 and important for rhythmicity in behavior Diurnal gene expression in the paraventricular nucleus (PVN) of the hypothalamus is highly dynamic and cell specific. Van Drunen et al. demonstrate mechanisms by which the circadian transcription factor BMAL1 drives PVN gene regulation and, subsequently, rhythmicity in energy intake and expenditure.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 AUTHOR CONTRIBUTIONS K.E.-M. and R.V.D. conceived the study with contributions from Q.T., J.Q.W., N.J., and S.-h.Y. R.V.D. performed experiments with contributions from B.F., S.N., S.S., and R.B. snRNA-seq analysis was carried out by Y.D. under the guidance of Z.Z. H.W. performed ChIP-seq analysis under guidance of J.W. Analysis of the snRNAseq and the ChIP-seq was carried out by R.V.D. and K.E.-M. R.V.D. and K.E.-M. wrote the manuscript with input from co-authors Q.T., J.Q.W., S.Y., and N.J. K.E.-M. supervised the study and was responsible for the funding.
ISSN:	2211-1247 2211-1247
DOI:	10.1016/j.celrep.2024.114380