title: The short-chain fatty acid receptor GPR43 is transcriptionally regulated by XBP1 in human monocytes.
abstract: G-protein coupled receptor 43 (GPR43) recognizes short chain fatty acids and is implicated in obesity, colitis, asthma and arthritis. Here, we present the first full characterization of the GPR43 promoter and 5'-UTR. 5'-RACE of the GPR43 transcript identified the transcription start site (TSS) and a 124 bp 5'-UTR followed by a 1335 bp intron upstream of the ATG start codon. The sequence spanning -4560 to +68 bp relative to the GPR43 TSS was found to contain strong promoter activity, increasing luciferase reporter expression by >100-fold in U937 monocytes. Stepwise deletions further narrowed the putative GPR43 promoter (-451 to +68). Site-directed mutagenesis identified XBP1 as a core cis element, the mutation of which abrogated transcriptional activity. Mutations of predicted CREB, CHOP, NFAT and STAT5 binding sites, partially reduced promoter activity. ChIP assays confirmed the binding of XBP1 to the endogenous GPR43 promoter. Consistently, GPR43 expression is reduced in monocytes upon siRNA-knockdown of XBP1, while A549 cells overexpressing XBP1 displayed elevated GPR43 levels. Based on its ability to activate XBP1, we predicted and confirmed that TNFα induces GPR43 expression in human monocytes. Altogether, our findings form the basis for strategic modulation of GPR43 expression, with a view to regulate GPR43-associated diseases.
authors: 1] Department of Biological Sciences, National University of Singapore, Singapore 117543 [2] NUS graduate School for Integrative Science and Engineering, National University of Singapore, Singapore 117543.
authors: Zhiwei
authors: Z
authors: Ang
authors: 1] Department of Biological Sciences, National University of Singapore, Singapore 117543 [2] NUS graduate School for Integrative Science and Engineering, National University of Singapore, Singapore 117543.
authors: Jun Zhi
authors: JZ
authors: Er
authors: 1] Department of Biological Sciences, National University of Singapore, Singapore 117543 [2] NUS graduate School for Integrative Science and Engineering, National University of Singapore, Singapore 117543.
authors: Jeak Ling
authors: JL
authors: Ding
mesh_terms: D000818:Animals; D020029:Base Pairing / Q000235:genetics; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D018387:Codon, Initiator / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004742:Enhancer Elements, Genetic / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D018345:Mice, Knockout; D008954:Models, Biological; D008969:Molecular Sequence Data; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D010641:Phenotype; D011401:Promoter Regions, Genetic; D011485:Protein Binding / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism; D000071701:Regulatory Factor X Transcription Factors; D017384:Sequence Deletion / Q000235:genetics; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D024363:Transcription Initiation Site; D014158:Transcription, Genetic / Q000187:drug effects; D010738:Type C Phospholipases / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D000071717:X-Box Binding Protein 1; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled
chemical_list: D018387:Codon, Initiator; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; D000071701:Regulatory Factor X Transcription Factors; D013755:Tetradecanoylphorbol Acetate; D014157:Transcription Factors; D010738:Type C Phospholipases; D000071717:X-Box Binding Protein 1; D048051:p38 Mitogen-Activated Protein Kinases; C473103:FFAR2 protein, human; D043562:Receptors, G-Protein-Coupled; C000605543:XBP1 protein, human; C000605544:Xbp1 protein, mouse
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