title: The zinc finger transcription factor ZXDC activates CCL2 gene expression by opposing BCL6-mediated repression.
abstract: The zinc finger X-linked duplicated (ZXD) family of transcription factors has been implicated in regulating transcription of major histocompatibility complex class II genes in antigen presenting cells; roles beyond this function are not yet known. The expression of one gene in this family, ZXD family zinc finger C (ZXDC), is enriched in myeloid lineages and therefore we hypothesized that ZXDC may regulate myeloid-specific gene expression. Here we demonstrate that ZXDC regulates genes involved in myeloid cell differentiation and inflammation. Overexpression of the larger isoform of ZXDC, ZXDC1, activates expression of monocyte-specific markers of differentiation and synergizes with phorbol 12-myristate 13-acetate (which causes differentiation) in the human leukemic monoblast cell line U937. To identify additional gene targets of ZXDC1, we performed gene expression profiling which revealed multiple inflammatory gene clusters regulated by ZXDC1. Using a combination of approaches we show that ZXDC1 activates transcription of a gene within one of the regulated clusters, chemokine (C-C motif) ligand 2 (CCL2; monocyte chemoattractant protein 1; MCP1) via a previously defined distal regulatory element. Further, ZXDC1-dependent up-regulation of the gene involves eviction of the transcriptional repressor B-cell CLL/lymphoma 6 (BCL6), a factor known to be important in resolving inflammatory responses, from this region of the promoter. Collectively, our data show that ZXDC1 is a regulator in the process of myeloid function and that ZXDC1 is responsible for Ccl2 gene de-repression by BCL6.
authors: Department of Biochemistry and Molecular Biology, University of Kansas School of Medicine, 3901 Rainbow Boulevard, MS3030, Kansas City, KS 66160, USA. Electronic address: jramsey@kumc.edu.
authors: Jon E
authors: JE
authors: Ramsey
authors: Joseph D
authors: JD
authors: Fontes
mesh_terms: D001483:Base Sequence; D015153:Blotting, Western; D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D020869:Gene Expression Profiling; D057809:HEK293 Cells; D006801:Humans; D018613:Microscopy, Confocal; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D051560:Proto-Oncogene Proteins c-bcl-6; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D020298:U937 Cells; D016335:Zinc Fingers / Q000235:genetics
chemical_list: C084103:BCL6 protein, human; D018932:Chemokine CCL2; D004268:DNA-Binding Proteins; D020033:Protein Isoforms; D051560:Proto-Oncogene Proteins c-bcl-6; D014157:Transcription Factors; C516737:ZXDC protein, human; D013755:Tetradecanoylphorbol Acetate
keywords: Chemokine; Gene regulation; Inflammation; Zinc finger transcription factor
references: Mol Cell Biol. 2008 Jul;28(13):4407-23
references: 18443042
references: Nat Rev Rheumatol. 2010 Mar;6(3):146-56
references: 20142813
references: J Immunol. 2003 Apr 15;170(8):4139-47
references: 12682245
references: Genes Dev. 1998 Jul 1;12(13):1953-61
references: 9649500
references: Mol Cell Biol. 2009 Aug;29(15):4156-66
references: 19487462
references: Methods Mol Biol. 2003;229:43-55
references: 12824620
references: Oncogene. 1998 Nov 12;17(19):2473-84
references: 9824158
references: Blood. 2010 Jul 1;115(26):5376-84
references: 20410506
references: Cell Metab. 2012 Apr 4;15(4):554-62
references: 22465074
references: Proc Natl Acad Sci U S A. 1996 Oct 15;93(21):11382-8
references: 8876144
references: Curr Opin Genet Dev. 2009 Apr;19(2):187-91
references: 19231154
references: Cold Spring Harb Protoc. 2012 Mar 01;2012(3):279-96
references: 22383646
references: Nat Genet. 2002 Dec;32(4):606-13
references: 12402037
references: Genes Dev. 2010 Dec 15;24(24):2760-5
references: 21106671
references: Nucleic Acids Res. 2010 Jul;38(Web Server issue):W755-62
references: 20513647
references: Nat Protoc. 2009;4(1):44-57
references: 19131956
references: Microsc Res Tech. 2003 Jul 1;61(4):389-407
references: 12811744
references: J Clin Invest. 2009 Jun;119(6):1714-26
references: 19451695
references: Oncogene. 1999 Sep 9;18(36):5063-75
references: 10490843
references: J Virol. 1998 Nov;72(11):8463-71
references: 9765382
references: Proc Natl Acad Sci U S A. 1997 Sep 30;94(20):10762-7
references: 9380707
references: Clin Exp Allergy. 2011 Nov;41(11):1568-78
references: 21801248
references: Nat Immunol. 2000 Sep;1(3):214-20
references: 10973278
references: J Biol Chem. 2002 Jun 14;277(24):22045-52
references: 11929873
references: Proc Natl Acad Sci U S A. 1996 Jul 9;93(14):6947-52
references: 8692924
references: Hum Gene Ther. 2011 Jan;22(1):93-100
references: 20626321
references: Mol Immunol. 2007 Jan;44(4):311-21
references: 16600381
references: J Immunol. 1994 Sep 1;153(5):2052-63
references: 8051410
references: Proc Natl Acad Sci U S A. 1995 Aug 15;92(17):8069-73
references: 7644539
references: Genes Dev. 2009 Mar 15;23(6):681-93
references: 19299558
references: Science. 2003 Oct 17;302(5644):453-7
references: 12970571
references: J Leukoc Biol. 1985 Apr;37(4):407-22
references: 3855947
references: EMBO J. 2005 Jan 12;24(1):85-96
references: 15616592
references: BMC Bioinformatics. 2010 Mar 09;11:121
references: 20214778
references: Genes Dev. 2000 Jul 15;14(14):1810-23
references: 10898795
references: Biochem Biophys Res Commun. 2003 Jan 10;300(2):391-6
references: 12504096
references: Nature. 2012 Jan 5;481(7379):90-3
references: 22113614
references: Curr Protoc Bioinformatics. 2009 Sep;Chapter 13:Unit 13.11
references: 19728287
references: Cold Spring Harb Protoc. 2009 Sep;2009(9):pdb.prot5279
references: 20147264
references: Cell Mol Immunol. 2004 Apr;1(2):95-104
references: 16212895
references: Nucleic Acids Res. 2009 Jan;37(1):1-13
references: 19033363
references: J Biol Chem. 2007 May 18;282(20):14797-806
references: 17392284
references: Blood. 1991 Aug 15;78(4):1112-6
references: 1868242
references: Mol Cell Biochem. 2010 Apr;337(1-2):1-7
references: 19777325
references: Mol Cell Biol. 2009 Aug;29(16):4394-405
references: 19506020
references: Methods. 2001 Dec;25(4):402-8
references: 11846609
references: Science. 1997 Apr 25;276(5312):589-92
references: 9110977
references: Oncogene. 1995 Dec 21;11(12):2689-97
references: 8545127
references: J Immunol. 1999 Jan 15;162(2):727-34
references: 9916692
references: J Mol Biol. 2007 Jun 22;369(5):1175-87
references: 17493635
references: Oncogene. 1997 May 22;14(20):2465-74
references: 9188861
references: Br J Cancer. 2009 Apr 21;100(8):1320-9
references: 19337254
references: Mol Cell Biol. 1995 Jan;15(1):315-25
references: 7799939
references: Endocrinology. 1995 Jun;136(6):2752-9
references: 7750500
references: Immunity. 1996 May;4(5):455-69
references: 8630731
references: Eur J Immunol. 1997 May;27(5):1091-7
references: 9174597
references: Biol Chem. 2007 Sep;388(9):965-72
references: 17696781
references: Mol Cell Biol. 2006 Aug;26(15):5759-70
references: 16847329
references: Nat Genet. 1997 Jun;16(2):161-70
references: 9171827
references: Infect Immun. 2002 Sep;70(9):4841-50
references: 12183528