Chromatin Remodeling： CHD.PDF

SnapShot:Chromatin Remodeling:CHDJennifer K.Sims and Paul A.WadeLaboratory of Molecular Carcinogenesis,NIEHS,Research Triangle Park,NC 27709,USASee online version for legend and references.626 Cell 144,February 18,2011 2011 Elsevier Inc.DOI 10.1016/j.cell.2011.02.019 RbAp46/48RbBp5Subfamily I:CHD1/CHD2Chromo domain cocrystalizedwith H3K4me3 peptideYEASTCHD1MonomerMonomerMonomerMonomerCHD2FLYHUMANNuRDUnknownUnknownUnknownCHD6-2-3MDacomplexCHD5CHD9CHD6/7/8dMecFLYHUMAN FLYHUMAN Nucleosome spacingNucleosome slidingMechanism unknownChromatin assemblySubfamily II:CHD3-5/Mi-2Subfamily III:CHD6-9CHD3/4dMi2PARP1WDR5Ash2LPBAFcomplexMTA1/2/3p66/MBD2/3HDAC1/2p66/68dRPD3dMBD2/3dMep1SAGA/SLIKcomplexCHD1HDAC1/2MBD2/3HDAC1/2CHD3/4complexCHD7CHD8KIS-LCHD6/7/8PHD domain 2 modeled with H3 peptideATPaseChromoChromoDNAbindingATPaseChromoChromoATPaseChromoChromoPHDPHDBRKSANTGeneral structure of CHD familyComplex membersRemodeling mechanisms/biological functionsATPADP+PiCHD1CHD1ATPADP+PiATPADP+PidMTAdMi2p55Core histonesCHD1:Maintenance of mouse embryonic stem cellsCHD2:Roles in mammalian development,DNA damageresponses,and tumor suppression CHD5:Potential tumor suppressor in breast,colon,andneuroectodermal cancersCHD6:Localizes to sites of transcription and is induced by DNA damageCHD7:Mutated in CHARGE syndrome;preferentially binds to distal regulatory elementsCHD8:Implicated in expression of small RNAs and of genes regulated by-catenin;represses p53 functionsCHD9:Regulates gene expression in osteoblastsCHD1CHD1CHD1CHD1CHD1NAP1Chromo domain cocrystalizedwith H3K4me3 peptideSubfamily II:CHD3-5/Mi-2ChromoChromoPHD domain 2 modeled with H3 peptide626.e1 Cell 144,February 18,2011 2011 Elsevier Inc.DOI 10.1016/j.cell.2011.02.019 SnapShot:Chromatin Remodeling:CHDJennifer K.Sims and Paul A.WadeLaboratory of Molecular Carcinogenesis,NIEHS,Research Triangle Park,NC 27709,USAThe CHD family of chromatin-remodeling complexes is defined by the presence(from amino to carboxy termini)of dual chromodomains,a DNA-dependent ATPase domain of the SNF2 superfamily,and,in some cases,a DNA-binding domain.The family is subdivided into three subfamilies based on the presence of additional sequence motifs.Subfamily 1(CHD1/CHD2)contains dual chromodomains,ATPase domain,and DNA-binding domain.Subfamily 2(CHD3/CHD4/CHD5)contains,in addition to the above,dual PHD fingers.Subfamily 3(CHD6/CHD7/CHD8/CHD9)contains dual chromodomains,an ATPase domain,a SANT domain,and a C-terminal BRK domain.Subfamily I(CHD1/CHD2)Subfamily I(CHD1/CHD2)is conserved from yeast to humans.Yeast CHD1 regulates transcriptional elongation via interaction with the Paf1 complex.Human CHD1 binds directly to histone H3 trimethylated at lysine 4 and associates with the spliceosome complex.In addition,CHD1 functions as an active chromatin assembly factor.Drosophila CHD1 is required for histone H3.3 deposition in vivo,and mouse CHD1 is important for the maintenance of embryonic stem cells.CHD2 is implicated in mammalian development,DNA damage responses,and tumor suppression.Subfamily II(CHD3/CHD4/CHD5)CHD3/CHD4 proteins are integral subunits of the Mi-2/NuRD chromatin-remodeling histone deacetylase complex.This complex functions in transcription,in replication-coupled chromatin assembly,and in DNA repair.CHD5 expression is largely confined to neural tissue,where its associations are not well characterized.It appears to have tumor-suppressive functions in tumors of breast,colon,and neuroectodermal origin.The chromodomain sequence of subfamily II differs significantly from that of either subfamily I or III,making it unlikely for them to interact with histone tails.In addition,biochemical studies have demonstrated that Drosophila Mi-2 is able to interact directly with“tailless”nucleosomes as well as with DNA under low-salt conditions.Subfamily III(CHD6/CHD7/CHD8/CHD9)The four vertebrate subfamily III members are homologs of a single Drosophila Trithorax-group protein,Kismet,involved in regulation of Hox gene expression,body segmenta-tion,and transcriptional elongation.CHD6 localizes to sites of transcription,is induced by DNA damage,and is a component of a large protein complex that remains largely uncharacterized.CHD7 is mutated in CHARGE syndrome,a developmental disorder affecting normal development of multiple tissues.CHD7 associates with BRG-1-containing SWI/SNF chromatin-remodeling complex and preferentially binds to distal regulatory elements,such as gene enhancers.The chromodomains of CHD7 interact directly with methylated histone H3 lysine 4.The CHD7 complex is required for the normal patterns of gene expression that are essential to the developmental program of neural crest cells.CHD8 and its associated complex interact with histone H3 di-and trimethylated at lysine 4 and have been implicated in normal expression of small RNAs and of genes regulated by b-catenin.CHD8 represses p53 functions and apoptosis during mammalian development and has been shown to interact with CHD7.CHD9 has been implicated in regulation of gene expression in osteoblasts and is dynamically phosphorylated.AbbreviationsCHARGE,coloboma,heart defects,atresia of the nasal choanae,retardation of growth,genital abnormalities,and ear abnormalities;SWI/SNF,switch/sucrose nonfermenting.AcknowledgmentsThis work was supported by the Intramural Research Program of the National Institute of Environmental Health Science,NIH(project number Z01ES101965 to PAW).We gratefully acknowledge helpful suggestions from S.Khorasanizadeh,T.Kutateladze,S.Venkatachalam,J.Wysocka,and members of the Wade laboratory.RefeRencesBajpai,R.,Chen,D.A.,Rada-Iglesias,A.,Zhang,J.,Xiong,Y.,Helms,J.,Chang,C.P.,Zhao,Y.,Swigut,T.,and Wysocka,J.(2010).CHD7 cooperates with PBAF to control multipotent neural crest formation.Nature 463,958962.Benayahu,D.,Shacham,N.,and Shur,I.(2007).Insights on the functional role of chromatin remodelers in osteogenic 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