eray1,21 21 leirIc DOI 10.1016/j.cell.2011.02.019 Cell 144 , February 18, 2011©2011 Elsevier Inc. 626 SnapShot: Chromatin Remodeling: CHD Jennifer K. Sims and Paul A. Wade Laboratory of Molecular Carcinogenesis, NIEHS, Research Triangle Park, NC 27709, USA
General structure of CHD family Complex members Remodeling mechanisms/biological functions Subfamily I: CHD1/CHD2 YEAST FLY HUMAN Nucleosome spacing
ATP ADP+Pi
CHD1 DNA SAGA/SLIK ATPase binding CHD1 complex Monomer Monomer ChromoChromo ChromoChromo CHD1 Chromatin assembly NAP1 Core histones
ATP ADP+Pi
CHD1
CHD2 Monomer Monomer CHD1: Maintenance of mouse embryonic stem cells
Chromo domain cocrystalized CHD2: Roles in mammalian development, DNA damage with H3K4me3 peptide responses, and tumor suppression
Subfamily II: CHD3-5/Mi-2 FLY HUMAN Nucleosome sliding
p55 MTA1/2/3 ATPase p66/68 p66α/β NuRD dMTA ATP ADP+Pi PHD PHD dMi2 CHD3/4 Chromo Chromo dRPD3 MBD2/3 HDAC1/2 dMBD2/3 CHD3/4 RbAp46/48
dMec dMi2 dMep1 CHD5: Potential tumor suppressor in breast, colon, and neuroectodermal cancers See online version for legend and references. and legend for version online See PHD domain 2 modeled with H3 peptide CHD5 Unknown Unknown
Subfamily III: CHD6-9 FLY HUMAN Mechanism unknown CHD6-2-3MDa complex CHD6: Localizes to sites of transcription and is induced by KIS-L PARP1 DNA damage SANT CHD6/7/8 PBAF CHD7 CHD7: Mutated in CHARGE syndrome; preferentially CHD6/7/8 complex ATPase BRK WDR5 binds to distal regulatory elements
Chromo Chromo RbBp5 CHD8 CHD8: Implicated in expression of small RNAs and of genes Ash2L regulated by β-catenin; represses p53 functions CHD9: Regulates gene expression in osteoblasts CHD9 Unknown SnapShot: Chromatin Remodeling: CHD Jennifer K. Sims and Paul A. Wade Laboratory of Molecular Carcinogenesis, NIEHS, Research Triangle Park, NC 27709, USA
The 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.
Abbreviations CHARGE, coloboma, heart defects, atresia of the nasal choanae, retardation of growth, genital abnormalities, and ear abnormalities; SWI/SNF, switch/sucrose nonfermenting.
Acknowledgments
This 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.
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