The leukocyte integrin gene CD11d is repressed by gut-enriched Kruppel-like factor 4 in myeloid cells.
The myeloid-specific leukocyte integrin CD11d encodes the alphaD subunit for the alphaDbeta2 receptor. A yeast one-hybrid screen showed that a longer isoform of gut-enriched Kruppel-like factor 4 (GKLF) we term GKLFa interacts with the CD11d promoter. Purified GST-GKLFa protein was shown to bind within the -61 to -44 region that overlaps a binding site for the CD11d transcriptional activators Sp1 and transforming growth factor beta-inducible early gene-1 (TIEG1). Transfection of GKLF/GKLFa in myeloid cells reduced CD11d promoter activity, whereas, down-regulation of GKLF/GKLFa with small interfering RNAs led to up-regulation of CD11d expression. Differentiation of myeloid cells with phorbol ester led to activation of the CD11d promoter and reduced occupancy of the promoter by GKLF/GKLFa but an increased occupancy by TIEG1 in vivo. Binding of GKLF/GKLFa, Sp1, and TIEG1 to the CD11d promoter in vivo is dependent on their zinc finger DNA binding domains. GKLFa physically associates with the histone deacetylases (HDAC) 1 and 2, and both HDACs are bound to the CD11d promoter in vivo but released after exposure of myeloid cells to phorbol ester suggesting that GKLF/GKLFa recruits HDACs to effect repression.
Noti
John D
JD
Guthrie Foundation for Education and Research, Sayre, Pennsylvania 18840, USA. noti_john@guthrie.org
Johnson
Andrew K
AK
Dillon
Jill D
JD
D000818:Animals; D018845:CD11 Antigens / Q000235:genetics*; D006528:Carcinoma, Hepatocellular; D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D015536:Down-Regulation; D018922:HL-60 Cells; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D039001:Integrin alpha Chains / Q000235:genetics*; D019169:Jurkat Cells; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D007948:Leukemia, Monocytic, Acute; D008113:Liver Neoplasms; D051379:Mice; D009101:Multiple Myeloma; D022423:Myeloid Cells / Q000502:physiology*; D011401:Promoter Regions, Genetic / Q000502:physiology; D034741:RNA, Small Interfering; D016329:Sp1 Transcription Factor / Q000378:metabolism; D018243:Teratocarcinoma; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D015854:Up-Regulation
D018845:CD11 Antigens; D004268:DNA-Binding Proteins; C406812:ITGAD protein, human; D039001:Integrin alpha Chains; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D034741:RNA, Small Interfering; D016329:Sp1 Transcription Factor; D014157:Transcription Factors; D006655:Histone Deacetylases