Cell-specific regulation of the circadian clock by BMAL1 in the paraventricular nucleus: Implications for regulation of systemic biological rhythms
Rachel Van Drunen,
Yulin Dai,
Haichao Wei,
Baharan Fekry,
Sina Noori,
Samay Shivshankar,
Rafael Bravo,
Zhongming Zhao,
Seung-hee Yoo,
Nicholas Justice,
Jia Qian Wu,
Qingchun Tong,
Kristin Eckel-Mahan
Affiliations
Rachel Van Drunen
UT Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA; MD Anderson Cancer Center/UTHealth Graduate School of Biomedical Sciences, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
Yulin Dai
Center for Precision Health, McWilliams School of Biomedical Informatics, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
Haichao Wei
UT Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA; Department of Neurosurgery, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
Baharan Fekry
UT Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
Sina Noori
UT Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
Samay Shivshankar
UT Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
Rafael Bravo
UT Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
Zhongming Zhao
Center for Precision Health, McWilliams School of Biomedical Informatics, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
Seung-hee Yoo
MD Anderson Cancer Center/UTHealth Graduate School of Biomedical Sciences, University of Texas Health Science Center at Houston, Houston, TX 77030, USA; Department of Biochemistry and Cell Biology, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
Nicholas Justice
UT Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA; MD Anderson Cancer Center/UTHealth Graduate School of Biomedical Sciences, University of Texas Health Science Center at Houston, Houston, TX 77030, USA; Department of Integrative Biology and Pharmacology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
Jia Qian Wu
UT Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA; MD Anderson Cancer Center/UTHealth Graduate School of Biomedical Sciences, University of Texas Health Science Center at Houston, Houston, TX 77030, USA; Department of Neurosurgery, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
Qingchun Tong
UT Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA; MD Anderson Cancer Center/UTHealth Graduate School of Biomedical Sciences, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
Kristin Eckel-Mahan
UT Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA; MD Anderson Cancer Center/UTHealth Graduate School of Biomedical Sciences, University of Texas Health Science Center at Houston, Houston, TX 77030, USA; Corresponding author
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.
