title: 1,25-Dihydroxyvitamin D regulates expression of the tryptophan hydroxylase 2 and leptin genes: implication for behavioral influences of vitamin D.
abstract: To investigate vitamin D-related control of brain-expressed genes, candidate vitamin D responsive elements (VDREs) at -7/-10 kb in human tryptophan hydroxylase (TPH)2 were probed. Both VDREs bound the vitamin D receptor (VDR)-retinoid X receptor (RXR) complex and drove reporter gene transcription in response to 1,25-dihydroxyvitamin D3 (1,25D). Brain TPH2 mRNA, encoding the rate-limiting enzyme in serotonin synthesis, was induced 2.2-fold by 10 nM 1,25D in human U87 glioblastoma cells and 47.8-fold in rat serotonergic RN46A-B14 cells. 1,25D regulation of leptin (Lep), encoding a serotoninlike satiety factor, was also examined. In mouse adipocytes, 1,25D repressed leptin mRNA levels by at least 84%, whereas 1,25D induced leptin mRNA 15.1-fold in human glioblastoma cells. Chromatin immunoprecipitation sequencing analysis of the mouse Lep gene in response to 1,25D revealed a cluster of regulatory sites (cis-regulatory module; CRM) at -28 kb that 1,25D-dependently docked VDR, RXR, C/EBPβ, and RUNX2. This CRM harbored 3 VDREs and single C/EBPβ and RUNX2 sites. Therefore, the expression of human TPH2 and mouse Lep are governed by 1,25D, potentially via respective VDREs located at -7/-10 kb and -28 kb. These results imply that vitamin D affects brain serotonin concentrations, which may be relevant to psychiatric disorders, such as autism, and may control leptin levels and affect eating behavior.
authors.affiliation: *Department of Basic Medical Sciences, University of Arizona College of Medicine, Phoenix, Arizona, USA; School of Mathematical and Natural Sciences, Arizona State University, Phoenix, Arizona, USA; and Department of Biochemistry, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Kaneko
authors.affiliation: *Department of Basic Medical Sciences, University of Arizona College of Medicine, Phoenix, Arizona, USA; School of Mathematical and Natural Sciences, Arizona State University, Phoenix, Arizona, USA; and Department of Biochemistry, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: Marya S
authors.initials: MS
authors.lastname: Sabir
authors.affiliation: *Department of Basic Medical Sciences, University of Arizona College of Medicine, Phoenix, Arizona, USA; School of Mathematical and Natural Sciences, Arizona State University, Phoenix, Arizona, USA; and Department of Biochemistry, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Dussik
authors.affiliation: *Department of Basic Medical Sciences, University of Arizona College of Medicine, Phoenix, Arizona, USA; School of Mathematical and Natural Sciences, Arizona State University, Phoenix, Arizona, USA; and Department of Biochemistry, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: G Kerr
authors.initials: GK
authors.lastname: Whitfield
authors.affiliation: *Department of Basic Medical Sciences, University of Arizona College of Medicine, Phoenix, Arizona, USA; School of Mathematical and Natural Sciences, Arizona State University, Phoenix, Arizona, USA; and Department of Biochemistry, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: Amitis
authors.initials: A
authors.lastname: Karrys
authors.affiliation: *Department of Basic Medical Sciences, University of Arizona College of Medicine, Phoenix, Arizona, USA; School of Mathematical and Natural Sciences, Arizona State University, Phoenix, Arizona, USA; and Department of Biochemistry, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: Jui-Cheng
authors.initials: JC
authors.lastname: Hsieh
authors.affiliation: *Department of Basic Medical Sciences, University of Arizona College of Medicine, Phoenix, Arizona, USA; School of Mathematical and Natural Sciences, Arizona State University, Phoenix, Arizona, USA; and Department of Biochemistry, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Haussler
authors.affiliation: *Department of Basic Medical Sciences, University of Arizona College of Medicine, Phoenix, Arizona, USA; School of Mathematical and Natural Sciences, Arizona State University, Phoenix, Arizona, USA; and Department of Biochemistry, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: Mark B
authors.initials: MB
authors.lastname: Meyer
authors.affiliation: *Department of Basic Medical Sciences, University of Arizona College of Medicine, Phoenix, Arizona, USA; School of Mathematical and Natural Sciences, Arizona State University, Phoenix, Arizona, USA; and Department of Biochemistry, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: J Wesley
authors.initials: JW
authors.lastname: Pike
authors.affiliation: *Department of Basic Medical Sciences, University of Arizona College of Medicine, Phoenix, Arizona, USA; School of Mathematical and Natural Sciences, Arizona State University, Phoenix, Arizona, USA; and Department of Biochemistry, University of Wisconsin-Madison, Madison, Wisconsin, USA pjurutka@asu.edu.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Jurutka
mesh_terms: D041721:3T3-L1 Cells; D000818:Animals; D001321:Autistic Disorder / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects*; D002117:Calcitriol / Q000494:pharmacology*; D045744:Cell Line, Tumor; D005247:Feeding Behavior / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects*; D057809:HEK293 Cells; D006801:Humans; D020738:Leptin / Q000096:biosynthesis*; D051379:Mice; D012333:RNA, Messenger / Q000096:biosynthesis; D020218:Response Elements / Q000187:drug effects; D014365:Tryptophan Hydroxylase / Q000096:biosynthesis*
chemical_list: D020738:Leptin; D012333:RNA, Messenger; C494784:TPH2 protein, human; C487802:Tph2 protein, mouse; D014365:Tryptophan Hydroxylase; D002117:Calcitriol
keywords: CNS; chromatin immunoprecipitation; cis-regulatory module; neuropsychiatric disorders; serotonin