title: An intronic Ikaros-binding element mediates retinoic acid suppression of the kappa opioid receptor gene, accompanied by histone deacetylation on the promoters.
abstract: The mouse kappa opioid receptor (KOR) gene is constitutively expressed in mouse embryonal carcinoma P19 stem cells and suppressed by retinoic acid (RA) in cells undergoing neuronal differentiation. A negative regulatory element is located within intron 1 of the KOR gene, which contains an Ikaros (Ik)-binding site (GGGAAgGGGAT). This sequence is an Ik-1 respondive, functionally negative element as demonstrated in the context of both natural KOR and heterologous promoters. The two underlined G residues of the second half-site are critical for Ik-1 binding and Ik-mediated repression of the KOR gene. RA induces Ik-1 expression within 1 day of treatment and suppresses KOR expression between 2 and 3 days. Overexpression of Ik-1 in P19 suppresses endogenous KOR gene expression, accompanied by increased binding of Ik-1 to the Ik-binding site and chromatin histone deacetylation on KOR promoters. It is proposed that in an RA-induced P19 differentiation model, RA elevates Ik-1 expression, which recruits histone deacetylase to intron 1 of the KOR gene and silences KOR gene promoters.
authors.affiliation: Department of Pharmacology, University of Minnesota Medical School, Minneapolis, MN 55455-0217, USA.
authors.forename: X
authors.initials: X
authors.lastname: Hu
authors.forename: J
authors.initials: J
authors.lastname: Bi
authors.forename: H H
authors.initials: HH
authors.lastname: Loh
authors.forename: L N
authors.initials: LN
authors.lastname: Wei
mesh_terms: D000107:Acetylation; D000818:Animals; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D020868:Gene Silencing; D006657:Histones / Q000378:metabolism; D051740:Ikaros Transcription Factor; D007438:Introns; D051379:Mice; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis; D017473:Receptors, Opioid, kappa / Q000096:biosynthesis / Q000235:genetics*; D012045:Regulatory Sequences, Nucleic Acid; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D004268:DNA-Binding Proteins; D006657:Histones; D012333:RNA, Messenger; D017473:Receptors, Opioid, kappa; D014157:Transcription Factors; C497238:Zfpn1a1 protein, mouse; D051740:Ikaros Transcription Factor; D014212:Tretinoin