title: Human fetal globin gene expression is regulated by LYAR.
abstract: Human globin gene expression during development is modulated by transcription factors in a stage-dependent manner. However, the mechanisms controlling the process are still largely unknown. In this study, we found that a nuclear protein, LYAR (human homologue of mouse Ly-1 antibody reactive clone) directly interacted with the methyltransferase PRMT5 which triggers the histone H4 Arg3 symmetric dimethylation (H4R3me2s) mark. We found that PRMT5 binding on the proximal γ-promoter was LYAR-dependent. The LYAR DNA-binding motif (GGTTAT) was identified by performing CASTing (cyclic amplification and selection of targets) experiments. Results of EMSA and ChIP assays confirmed that LYAR bound to a DNA region corresponding to the 5'-untranslated region of the γ-globin gene. We also found that LYAR repressed human fetal globin gene expression in both K562 cells and primary human adult erythroid progenitor cells. Thus, these data indicate that LYAR acts as a novel transcription factor that binds the γ-globin gene, and is essential for silencing the γ-globin gene.
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, China.
authors.forename: Junyi
authors.initials: J
authors.lastname: Ju
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, China.
authors.forename: Ronghua
authors.initials: R
authors.lastname: Liu
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, China.
authors.forename: Yichong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Xu
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, China.
authors.forename: Yadong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, China.
authors.forename: Yupeng
authors.initials: Y
authors.lastname: Wu
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Medicine, Monash University Central Clinical School, Prahran, VIC 3181, Australia.
authors.forename: Loretta
authors.initials: L
authors.lastname: Cerruti
authors.affiliation: Department of Chemistry, Northwestern University, Evanston, IL 60208, USA.
authors.forename: Fengwei
authors.initials: F
authors.lastname: Zou
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, China.
authors.forename: Chi
authors.initials: C
authors.lastname: Ma
authors.affiliation: Institute of Life Sciences, Southeast University, Nanjing 210096, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Fang
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, China.
authors.forename: Renxiang
authors.initials: R
authors.lastname: Tan
authors.affiliation: Department of Medicine, Monash University Central Clinical School, Prahran, VIC 3181, Australia qzhao@nju.edu.cn.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Jane
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, China qzhao@nju.edu.cn.
authors.forename: Quan
authors.initials: Q
authors.lastname: Zhao
mesh_terms: D020121:5' Untranslated Regions; D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D016384:Consensus Sequence; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D041905:Erythroid Cells / Q000166:cytology / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D020868:Gene Silencing; D006801:Humans; D020014:K562 Cells; D051379:Mice; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D011484:Protein-Arginine N-Methyltransferases / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D055545:gamma-Globins / Q000235:genetics* / Q000378:metabolism
chemical_list: D020121:5' Untranslated Regions; D004268:DNA-Binding Proteins; C000592018:LYAR protein, human; C081182:Lyar protein, mouse; D009687:Nuclear Proteins; D012097:Repressor Proteins; D055545:gamma-Globins; C400529:PRMT5 protein, human; D011484:Protein-Arginine N-Methyltransferases
references.citation: Proc Natl Acad Sci U S A. 2006 Apr 25;103(17):6617-22
references.pmid: 16608912
references.citation: Exp Hematol. 2005 Mar;33(3):259-71
references.pmid: 15730849
references.citation: Mt Sinai J Med. 2005 Sep;72(5):333-8
references.pmid: 16184297
references.citation: Nature. 1959 Dec 12;184(Suppl 24):1877-8
references.pmid: 13800165
references.citation: Proc Natl Acad Sci U S A. 2010 Apr 13;107(15):6864-9
references.pmid: 20351289
references.citation: J Biol Chem. 1994 Jan 14;269(2):1493-500
references.pmid: 8288615
references.citation: Blood. 2006 Jan 15;107(2):435-43
references.pmid: 16109777
references.citation: Science. 2008 Dec 19;322(5909):1839-42
references.pmid: 19056937
references.citation: Hum Mol Genet. 2007 Sep 15;16(18):2226-32
references.pmid: 17616513
references.citation: Mol Cell Biol. 2005 Feb;25(4):1215-27
references.pmid: 15684376
references.citation: Nat Struct Mol Biol. 2009 Mar;16(3):304-311
references.pmid: 19234465
references.citation: PLoS One. 2012;7(10):e47175
references.pmid: 23071749
references.citation: Blood Cells Mol Dis. 2009 Mar-Apr;42(2):144-9
references.pmid: 19153051
references.citation: Trends Biochem Sci. 2011 Jul;36(7):364-72
references.pmid: 21514168
references.citation: Int J Lab Hematol. 2012 Feb;34(1):1-13
references.pmid: 21974826
references.citation: Blood. 2006 Aug 1;108(3):1077-83
references.pmid: 16861354
references.citation: J Biol Chem. 2004 Jun 18;279(25):26227-32
references.pmid: 15084587
references.citation: Mol Cell Biol. 2000 Oct;20(20):7662-72
references.pmid: 11003662
references.citation: EMBO J. 2002 Jul 1;21(13):3434-42
references.pmid: 12093744
references.citation: Proc Natl Acad Sci U S A. 2000 Jun 20;97(13):7172-7
references.pmid: 10840054
references.citation: Blood. 2007 Sep 15;110(6):1933-41
references.pmid: 17505015
references.citation: Neuropharmacology. 2011 Jun;60(7-8):1075-87
references.pmid: 20869372
references.citation: Ann N Y Acad Sci. 2010 Aug;1202:17-23
references.pmid: 20712767
references.citation: Genes Dev. 1993 May;7(5):735-48
references.pmid: 8491376
references.citation: Exp Hematol. 2009 Aug;37(8):889-900
references.pmid: 19447160
references.citation: EMBO J. 1995 Jan 3;14(1):97-105
references.pmid: 7828600
references.citation: Proc Natl Acad Sci U S A. 2011 Nov 15;108(46):18808-13
references.pmid: 22042865
references.citation: Mol Immunol. 2012 Oct;52(3-4):165-73
references.pmid: 22673213
references.citation: Blood. 2010 Sep 2;116(9):1585-92
references.pmid: 20495075
references.citation: Stem Cells. 2009 Jun;27(6):1244-54
references.pmid: 19489080
references.citation: Genes Dev. 2010 Apr 15;24(8):783-98
references.pmid: 20395365
references.citation: Mol Cell Biol. 2009 Mar;29(6):1526-37
references.pmid: 19114560
references.citation: Nature. 1995 May 25;375(6529):316-8
references.pmid: 7753194
references.citation: Blood. 2000 Jun 1;95(11):3578-84
references.pmid: 10828046
references.citation: Blood. 1992 Mar 1;79(5):1342-6
references.pmid: 1536956
references.citation: IUBMB Life. 2009 Aug;61(8):800-30
references.pmid: 19621348
references.citation: Blood. 2012 Oct 11;120(15):2945-53
references.pmid: 22904296
references.citation: Mol Cell Biol. 1999 May;19(5):3571-9
references.pmid: 10207080
references.citation: Nucleic Acids Res. 1990 Sep 11;18(17):5245-53
references.pmid: 1698280
references.citation: Dev Dyn. 2006 Jul;235(7):1727-37
references.pmid: 16607652
references.citation: Proc Natl Acad Sci U S A. 1996 Oct 29;93(22):12355-8
references.pmid: 8901585
references.citation: Blood. 2011 Sep 29;118(13):3684-93
references.pmid: 21828133
references.citation: Proc Natl Acad Sci U S A. 2012 Oct 30;109(44):17960-5
references.pmid: 23071334
references.citation: Nature. 2009 Aug 27;460(7259):1093-7
references.pmid: 19657335
references.citation: J Biol Chem. 1997 Aug 8;272(32):20030-7
references.pmid: 9242673
references.citation: Blood. 1992 Aug 1;80(3):575-81
references.pmid: 1638017
references.citation: Cancer Res. 2007 Nov 1;67(21):10491-500
references.pmid: 17974993
references.citation: Trends Biochem Sci. 1993 Mar;18(3):77-80
references.pmid: 8386867
references.citation: J Struct Biol. 2012 Oct;180(1):165-73
references.pmid: 22820306
references.citation: Nat Genet. 2010 Sep;42(9):742-4
references.pmid: 20676097
references.citation: PLoS One. 2012;7(4):e34327
references.pmid: 22523547
references.citation: Blood. 2010 Nov 18;116(20):4349-52
references.pmid: 20688955
references.citation: Nature. 1995 May 25;375(6529):318-22
references.pmid: 7753195