title: Global H3K4me3 genome mapping reveals alterations of innate immunity signaling and overexpression of JMJD3 in human myelodysplastic syndrome CD34+ cells.
abstract: The molecular bases of myelodysplastic syndromes (MDS) are not fully understood. Trimethylated histone 3 lysine 4 (H3K4me3) is present in promoters of actively transcribed genes and has been shown to be involved in hematopoietic differentiation. We performed a genome-wide H3K4me3 CHIP-Seq (chromatin immunoprecipitation coupled with whole genome sequencing) analysis of primary MDS bone marrow (BM) CD34+ cells. This resulted in the identification of 36 genes marked by distinct higher levels of promoter H3K4me3 in MDS. A majority of these genes are involved in nuclear factor (NF)-κB activation and innate immunity signaling. We then analyzed expression of histone demethylases and observed significant overexpression of the JmjC-domain histone demethylase JMJD3 (KDM6b) in MDS CD34+ cells. Furthermore, we demonstrate that JMJD3 has a positive effect on transcription of multiple CHIP-Seq identified genes involved in NF-κB activation. Inhibition of JMJD3 using shRNA in primary BM MDS CD34+ cells resulted in an increased number of erythroid colonies in samples isolated from patients with lower-risk MDS. Taken together, these data indicate the deregulation of H3K4me3 and associated abnormal activation of innate immunity signals have a role in the pathogenesis of MDS and that targeting these signals may have potential therapeutic value in MDS.
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Wei
authors.forename: R
authors.initials: R
authors.lastname: Chen
authors.forename: S
authors.initials: S
authors.lastname: Dimicoli
authors.forename: C
authors.initials: C
authors.lastname: Bueso-Ramos
authors.forename: D
authors.initials: D
authors.lastname: Neuberg
authors.forename: S
authors.initials: S
authors.lastname: Pierce
authors.forename: H
authors.initials: H
authors.lastname: Wang
authors.forename: H
authors.initials: H
authors.lastname: Yang
authors.forename: Y
authors.initials: Y
authors.lastname: Jia
authors.forename: H
authors.initials: H
authors.lastname: Zheng
authors.forename: Z
authors.initials: Z
authors.lastname: Fang
authors.forename: M
authors.initials: M
authors.lastname: Nguyen
authors.forename: I
authors.initials: I
authors.lastname: Ganan-Gomez
authors.forename: B
authors.initials: B
authors.lastname: Ebert
authors.forename: R
authors.initials: R
authors.lastname: Levine
authors.forename: H
authors.initials: H
authors.lastname: Kantarjian
authors.forename: G
authors.initials: G
authors.lastname: Garcia-Manero
mesh_terms: D018952:Antigens, CD34 / Q000378:metabolism*; D015153:Blotting, Western; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D047369:Chromatin Immunoprecipitation; D002874:Chromosome Mapping; D006657:Histones / Q000235:genetics*; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D007124:Immunoenzyme Techniques; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics* / Q000378:metabolism; D008239:Lysine / Q000235:genetics*; D009190:Myelodysplastic Syndromes / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
chemical_list: D018952:Antigens, CD34; D006657:Histones; D016328:NF-kappa B; D012333:RNA, Messenger; D056484:Jumonji Domain-Containing Histone Demethylases; C524220:KDM6B protein, human; D008239:Lysine
references.citation: J Immunol. 2011 May 1;186(9):5367-75
references.pmid: 21441445
references.citation: Curr Opin Cell Biol. 2012 Jun;24(3):374-86
references.pmid: 22513113
references.citation: Cell. 2010 Mar 19;140(6):805-20
references.pmid: 20303872
references.citation: J Immunol. 2000 Nov 1;165(9):5287-94
references.pmid: 11046063
references.citation: Nature. 2012 Aug 16;488(7411):404-8
references.pmid: 22842901
references.citation: N Engl J Med. 2009 Nov 5;361(19):1872-85
references.pmid: 19890130
references.citation: Dev Cell. 2008 May;14(5):798-809
references.pmid: 18477461
references.citation: Genes Dev. 2009 May 15;23(10):1171-6
references.pmid: 19451217
references.citation: J Immunol. 2003 Sep 15;171(6):3296-302
references.pmid: 12960360
references.citation: Bioinformatics. 2009 Jul 15;25(14):1754-60
references.pmid: 19451168
references.citation: J Exp Med. 1998 Dec 7;188(11):2083-90
references.pmid: 9841922
references.citation: J Biol Chem. 1999 Oct 22;274(43):30353-6
references.pmid: 10521409
references.citation: Cell. 2001 Oct 5;107(1):27-41
references.pmid: 11595183
references.citation: Blood. 2000 May 15;95(10):3223-31
references.pmid: 10807793
references.citation: EMBO J. 2009 Nov 4;28(21):3341-52
references.pmid: 19779457
references.citation: Hum Pathol. 2004 Feb;35(2):246-53
references.pmid: 14991544
references.citation: J Immunol. 1999 Dec 15;163(12):6777-84
references.pmid: 10586077
references.citation: Genome Res. 2010 Sep;20(9):1297-303
references.pmid: 20644199
references.citation: N Engl J Med. 2011 Oct 13;365(15):1384-95
references.pmid: 21995386
references.citation: J Immunol. 2010 Oct 15;185(8):4921-7
references.pmid: 20861352
references.citation: Blood. 2006 Feb 1;107(3):1156-65
references.pmid: 16223780
references.citation: Cell. 2007 Sep 21;130(6):1083-94
references.pmid: 17825402
references.citation: Cell. 2006 Apr 21;125(2):315-26
references.pmid: 16630819
references.citation: Leukemia. 2010 Apr;24(4):756-64
references.pmid: 20220779
references.citation: Annu Rev Immunol. 1999;17:931-72
references.pmid: 10358778
references.citation: Genes Dev. 2012 Jun 15;26(12):1364-75
references.pmid: 22713873
references.citation: Blood. 2012 Feb 9;119(6):1532-42
references.pmid: 22160620
references.citation: Leukemia. 2009 Apr;23(4):664-72
references.pmid: 19151777
references.citation: Immunity. 2006 Jun;24(6):801-812
references.pmid: 16782035
references.citation: Nature. 2010 Apr 8;464(7290):852-7
references.pmid: 20305640
references.citation: Infect Immun. 2005 Dec;73(12):8089-99
references.pmid: 16299303
references.citation: Cell. 2007 May 18;129(4):823-37
references.pmid: 17512414
references.citation: Nat Med. 2007 Sep;13(9):1042-9
references.pmid: 17767165
references.citation: Genome Biol. 2008;9(9):R137
references.pmid: 18798982
references.citation: J Clin Oncol. 2011 May 20;29(15):1963-70
references.pmid: 21519021
references.citation: N Engl J Med. 2011 Jun 30;364(26):2496-506
references.pmid: 21714648
references.citation: J Immunol. 1999 Dec 1;163(11):6095-105
references.pmid: 10570299
references.citation: J Clin Oncol. 2011 Feb 10;29(5):504-15
references.pmid: 21220588
references.citation: Nature. 2007 Nov 15;450(7168):415-9
references.pmid: 17928865
references.citation: Genes Dev. 1994 Feb 15;8(4):387-98
references.pmid: 8125254
references.citation: Immunity. 2000 Sep;13(3):355-64
references.pmid: 11021533
references.citation: Cell. 2009 Dec 24;139(7):1243-54
references.pmid: 20064371
references.citation: J Immunol. 1994 Apr 15;152(8):4080-6
references.pmid: 8144973
references.citation: J Clin Oncol. 2011 Feb 10;29(5):516-23
references.pmid: 21220589
references.citation: Blood. 2004 Jul 15;104(2):579-85
references.pmid: 15039286
references.citation: J Immunol. 2006 Nov 1;177(9):6182-91
references.pmid: 17056547
references.citation: Nature. 2001 Nov 15;414(6861):258-61
references.pmid: 11713509
references.citation: J Biol Chem. 2007 Dec 14;282(50):36190-8
references.pmid: 17942403
references.citation: J Cutan Pathol. 2008 Feb;35(2):180-5
references.pmid: 18190442
references.citation: J Immunol. 2000 Mar 1;164(5):2281-4
references.pmid: 10679061
references.citation: J Exp Med. 2003 May 5;197(9):1107-17
references.pmid: 12719479
references.citation: Genes Dev. 2008 Jul 15;22(14):1865-70
references.pmid: 18628393
references.citation: Blood. 1995 Jan 1;85(1):194-202
references.pmid: 7528567
references.citation: J Cell Sci. 2001 Dec;114(Pt 23):4307-18
references.pmid: 11739662
references.citation: J Natl Cancer Inst Monogr. 2008;(39):64-8
references.pmid: 18648006
references.citation: Mol Cell. 2010 Nov 24;40(4):594-605
references.pmid: 21095589
references.citation: Blood. 1997 Mar 15;89(6):2079-88
references.pmid: 9058730
references.citation: Proc Natl Acad Sci U S A. 2001 Dec 4;98(25):14577-82
references.pmid: 11724962
references.citation: J Biol Chem. 1989 Jan 25;264(3):1760-6
references.pmid: 2912983
references.citation: Nat Med. 2010 Jan;16(1):49-58
references.pmid: 19898489