title: Signal transducer and activator of transcription 6 directly regulates human ORMDL3 expression.
abstract: Orosomucoid-like 3 (ORMDL3) has been associated with asthma and a series of autoimmune disorders, and is involved in endoplasmic reticulum-mediated inflammatory responses. However, its clinical significance and the molecular mechanism underlying its expression are still largely unclear. To elucidate the mechanisms of human ORMDL3 transcriptional regulation, we cloned a 1.5 kb genomic DNA fragment containing the putative promoter region and evaluated its transcriptional activity in a luciferase reporter system by deletion analysis. We identified a 68 bp region that functions as a minimal promoter. Bioinformatics analysis predicted that the -64 to -56 bp region contained a signal transducer and activator of transcription 6 (STAT6) binding site. Electrophoretic mobility shift assay and chromatin immunoprecipitation demonstrated that STAT6 bound to its binding site within the ORMDL3 promoter. STAT6 over-expression or knockdown trans-activated or trans-inhibited, respectively, the ORMDL3 promoter containing the STAT6-binding motif. Treatment with interleukins 4 or 13 increased ORMDL3 promoter activity as well as endogenous ORMDL3 expression. Immunoprecipitation and ChIP/Re-ChIP assays revealed that STAT6 and p300 exist in the same protein complex that binds to the ORMDL3 promoter. Our study confirmed that STAT6 plays important roles in regulating the expression of human ORMDL3 by directly binding to the promoter region, which may shed light on a possible role in various human diseases.
authors: Department of Medical Genetics and Key Laboratory for Experimental Teratology of the Ministry of Education, Shandong University School of Medicine, Jinan, China.
authors: Rongfang
authors: R
authors: Qiu
authors: Yang
authors: Y
authors: Yang
authors: Hailing
authors: H
authors: Zhao
authors: Jiangxia
authors: J
authors: Li
authors: Qian
authors: Q
authors: Xin
authors: Shan
authors: S
authors: Shan
authors: Yongchao
authors: Y
authors: Liu
authors: Jie
authors: J
authors: Dang
authors: Xiao
authors: X
authors: Yu
authors: Yaoqin
authors: Y
authors: Gong
authors: Qiji
authors: Q
authors: Liu
mesh_terms: D001483:Base Sequence; D001665:Binding Sites; D045744:Cell Line, Tumor; D016384:Consensus Sequence; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D017930:Genes, Reporter; D057809:HEK293 Cells; D006801:Humans; D018793:Interleukin-13 / Q000502:physiology; D015847:Interleukin-4 / Q000502:physiology; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D050800:STAT6 Transcription Factor / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D015533:Transcriptional Activation
chemical_list: C578095:IL13 protein, human; C508598:IL4 protein, human; D018793:Interleukin-13; D008565:Membrane Proteins; C464399:ORMDL3 protein, human; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D015847:Interleukin-4