title: Regulation of MEIS1 by distal enhancer elements in acute leukemia.
abstract: Aberrant activation of the three-amino-acid-loop extension homeobox gene MEIS1 shortens the latency and accelerates the onset and progression of acute leukemia, yet the molecular mechanism underlying persistent activation of the MEIS1 gene in leukemia remains poorly understood. Here we used a combined comparative genomics analysis and an in vivo transgenic zebrafish assay to identify six regulatory DNA elements that are able to direct green fluorescent protein expression in a spatiotemporal manner during zebrafish embryonic hematopoiesis. Analysis of chromatin characteristics and regulatory signatures suggests that many of these predicted elements are potential enhancers in mammalian hematopoiesis. Strikingly, one of the enhancer elements (E9) is a frequent integration site in retroviral-induced mouse acute leukemia. The genomic region corresponding to enhancer E9 is differentially marked by H3K4 monomethylation and H3K27 acetylation, hallmarks of active enhancers, in multiple leukemia cell lines. Decreased enrichment of these histone marks is associated with downregulation of MEIS1 expression during hematopoietic differentiation. Further, MEIS1/HOXA9 transactivate this enhancer via a conserved binding motif in vitro, and participate in an autoregulatory loop that modulates MEIS1 expression in vivo. Our results suggest that an intronic enhancer regulates the expression of MEIS1 in hematopoiesis and contributes to its aberrant expression in acute leukemia.
authors.affiliation: 1] Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA [2] CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Q F
authors.initials: QF
authors.lastname: Wang
authors.affiliation: 1] CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China [2] Beijing Institute of Traditional Chinese Medicine, Beijing Hospital of Traditional Chinese Medicine Affiliated to Capital Medical University, Beijing, China.
authors.forename: Y J
authors.initials: YJ
authors.lastname: Li
authors.affiliation: Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA.
authors.forename: J F
authors.initials: JF
authors.lastname: Dong
authors.affiliation: CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.
authors.forename: B
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA.
authors.forename: J J
authors.initials: JJ
authors.lastname: Kaberlein
authors.affiliation: CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Human Genetics, University of Chicago, Chicago, IL, USA.
authors.forename: F E
authors.initials: FE
authors.lastname: Arimura
authors.affiliation: Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA.
authors.forename: R T
authors.initials: RT
authors.lastname: Luo
authors.affiliation: Tongji Medical College of Huazhong, University of Science & Technology, Wuhan, China.
authors.forename: J
authors.initials: J
authors.lastname: Ni
authors.affiliation: CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.
authors.forename: F
authors.initials: F
authors.lastname: He
authors.affiliation: CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.
authors.forename: J
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA.
authors.forename: R
authors.initials: R
authors.lastname: Mattison
authors.affiliation: CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.
authors.forename: J
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Anesthesia & Critical Care, University of Chicago, Chicago, IL, USA.
authors.forename: C Z
authors.initials: CZ
authors.lastname: Wang
authors.affiliation: Genome Institute of Singapore, Singapore.
authors.forename: S
authors.initials: S
authors.lastname: Prabhakar
authors.affiliation: Department of Human Genetics, University of Chicago, Chicago, IL, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Nobrega
authors.affiliation: Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Thirman
mesh_terms: D000208:Acute Disease; D000818:Animals; D004742:Enhancer Elements, Genetic; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007938:Leukemia / Q000235:genetics*; D051379:Mice; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins / Q000235:genetics*
chemical_list: D018398:Homeodomain Proteins; C000616391:MEIS1 protein, human; C000616392:Meis1 protein, mouse; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins
references.citation: Nucleic Acids Res. 2004 Jul 1;32(Web Server issue):W273-9
references.pmid: 15215394
references.citation: Exp Hematol. 2005 Sep;33(9):1007-14
references.pmid: 16140148
references.citation: Nature. 2001 Nov 8;414(6860):216-20
references.pmid: 11700560
references.citation: Mol Cell Biol. 2009 Sep;29(18):5181-92
references.pmid: 19620287
references.citation: Nucleic Acids Res. 2004 Jan 1;32(Database issue):D523-7
references.pmid: 14681473
references.citation: Exp Hematol. 2010 Sep;38(9):798-8, 808.e1-2
references.pmid: 20600580
references.citation: Blood. 2010 Apr 29;115(17):3642-3
references.pmid: 20430967
references.citation: Genome Res. 2008 Feb;18(2):201-5
references.pmid: 18245453
references.citation: Nat Protoc. 2006;1(3):1297-305
references.pmid: 17406414
references.citation: Genome Res. 2006 Jul;16(7):855-63
references.pmid: 16769978
references.citation: Leukemia. 2005 Jun;19(6):953-64
references.pmid: 15815718
references.citation: Leukemia. 2008 Mar;22(3):665-7
references.pmid: 17805329
references.citation: Blood. 2001 Aug 1;98(3):643-51
references.pmid: 11468162
references.citation: Leukemia. 2012 Apr;26(4):848-53
references.pmid: 21986840
references.citation: Proc Natl Acad Sci U S A. 2010 Dec 14;107(50):21931-6
references.pmid: 21106759
references.citation: Mol Cell Biol. 2004 Jan;24(2):617-28
references.pmid: 14701735
references.citation: Nature. 2007 Jun 14;447(7146):799-816
references.pmid: 17571346
references.citation: Biochem Biophys Res Commun. 2008 Oct 3;374(4):647-52
references.pmid: 18656453
references.citation: Science. 2003 Jun 13;300(5626):1670-1
references.pmid: 12805525
references.citation: Blood. 2012 Jan 12;119(2):388-98
references.pmid: 22072553
references.citation: Exp Hematol. 2002 Jan;30(1):49-57
references.pmid: 11823037
references.citation: Bioessays. 2000 Oct;22(10):882-93
references.pmid: 10984714
references.citation: Leukemia. 1999 Dec;13(12):1993-9
references.pmid: 10602420
references.citation: Genome Res. 2005 Aug;15(8):1034-50
references.pmid: 16024819
references.citation: Exp Hematol. 2005 Sep;33(9):997-1006
references.pmid: 16140147
references.citation: Cell Stem Cell. 2010 Oct 8;7(4):532-44
references.pmid: 20887958
references.citation: Br J Haematol. 2002 Oct;119(1):119-21
references.pmid: 12358913
references.citation: Blood. 2009 Feb 19;113(8):1756-8
references.pmid: 19109563
references.citation: Nucleic Acids Res. 2004 Jul 1;32(Web Server issue):W280-6
references.pmid: 15215395
references.citation: Am J Obstet Gynecol. 2006 Apr;194(4):1100-7; discussion 1107-9
references.pmid: 16580301
references.citation: PLoS One. 2012;7(3):e33617
references.pmid: 22448256
references.citation: Leukemia. 2005 Apr;19(4):636-43
references.pmid: 15744344
references.citation: Nature. 2011 Feb 10;470(7333):279-83
references.pmid: 21160473
references.citation: Oncogene. 2001 Feb 15;20(7):874-8
references.pmid: 11314021
references.citation: Nature. 2009 May 7;459(7243):108-12
references.pmid: 19295514
references.citation: Immunity. 2010 Mar 26;32(3):317-28
references.pmid: 20206554
references.citation: Blood. 2005 May 1;105(9):3502-11
references.pmid: 15644413
references.citation: Blood. 2012 Aug 2;120(5):1118-29
references.pmid: 22740449
references.citation: Nat Genet. 2007 Mar;39(3):311-8
references.pmid: 17277777
references.citation: Genome Res. 2008 Feb;18(2):252-60
references.pmid: 18071029
references.citation: Curr Opin Genet Dev. 2009 Apr;19(2):127-34
references.pmid: 19299119
references.citation: Leukemia. 1999 Oct;13(10):1525-33
references.pmid: 10516753
references.citation: Proc Natl Acad Sci U S A. 2011 May 10;108(19):7956-61
references.pmid: 21518888
references.citation: Acta Haematol. 2006;116(2):77-89
references.pmid: 16914901
references.citation: Blood. 2009 Mar 12;113(11):2375-85
references.pmid: 19056693
references.citation: Nat Rev Genet. 2004 Jun;5(6):456-65
references.pmid: 15153998
references.citation: Genome Res. 2006 May;16(5):656-68
references.pmid: 16606704
references.citation: EMBO J. 2004 Jan 28;23(2):450-9
references.pmid: 14713950
references.citation: Circ Res. 2008 Sep 26;103(7):702-9
references.pmid: 18723445
references.citation: Genomics. 1997 Jul 1;43(1):99-103
references.pmid: 9226379
references.citation: Genes Dev. 2007 Nov 1;21(21):2762-74
references.pmid: 17942707
references.citation: Genome Res. 2003 Apr;13(4):721-31
references.pmid: 12654723
references.citation: Mol Cell Biol. 1995 Oct;15(10):5434-43
references.pmid: 7565694
references.citation: Leukemia. 1999 May;13(5):687-98
references.pmid: 10374871
references.citation: Cancer Cell. 2011 Jul 12;20(1):39-52
references.pmid: 21741595
references.citation: Leukemia. 2013 Jun;27(6):1224-8
references.pmid: 23515098
references.citation: Blood. 2011 Jun 23;117(25):6895-905
references.pmid: 21518926