The Chd family of chromatin remodelers

Department of Cell Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis (Impact Factor: 4.44). 06/2007; 618(1-2):30-40. DOI: 10.1016/j.mrfmmm.2006.07.012
Source: PubMed

ABSTRACT Chromatin remodeling enzymes contribute to the dynamic changes that occur in chromatin structure during cellular processes such as transcription, recombination, repair, and replication. Members of the chromodomain helicase DNA-binding (Chd) family of enzymes belong to the SNF2 superfamily of ATP-dependent chromatin remodelers. The Chd proteins are distinguished by the presence of two N-terminal chromodomains that function as interaction surfaces for a variety of chromatin components. Genetic, biochemical, and structural studies demonstrate that Chd proteins are important regulators of transcription and play critical roles during developmental processes. Numerous Chd proteins are also implicated in human disease.

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Available from: Anthony N Imbalzano, Feb 27, 2014
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    • "This unique approach suggests a significant role for alterations in these chromatin factors in PCa. There has been increased interest in the CHD family [13] [14] given the finding of inactivation of other family members in disease including the recent findings of somatic mutation of CHD5 [31] and deletion of CHD1 [32]. CHD8 exhibits a functional dichotomy operating in both growth inhibitory and promoting roles including chromatin remodeling, WNT signaling, CTCF insulator activity, p53-mediated apoptosis, androgen receptor mediated gene activity, and regulation of cell cycle genes [33]. "
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    ABSTRACT: Abnormal expression and function of chromatin regulators results in the altered chromatin structure seen in cancer. The chromatin regulator CTCF, its cofactor CHD8, and antagonistic paralogue BORIS have wide-ranging effects on gene regulation. Their concurrent expression and regulation was examined in benign, localized, and metastatic prostate cancer (PCa) arrays with extended follow-up using an automated quantitative imaging system, VECTRA. Epithelial staining was quantified and compared against a range of clinicopathologic variables. CHD8 expression was decreased in HGPIN, localized, and metastatic PCa compared to benign (P < .001). CHD8 promoter hypermethylation, assessed by Quantitative Pyrosequencing, occurred in over 45% of primary cancers in this population as well as the TGCA database. Treatment of cell lines with the demethylating agent 5-Aza-2'-deoxycytidine reinduced expression. An interesting dichotomy for CHD8 was observed within primary cancers, with higher nuclear protein expression associated with adverse clinical outcomes including extracapsular extension (P = .007), presence of metastases (P = .025) and worse PSA-recurrence free survival (P = .048). CHD8 outperformed Gleason score and predicted biochemical failure within intermediate grade prostate cancers. The BORIS/CTCF expression ratio increased in localized (P = .03) and metastatic PCa (P = .006) and was associated with higher Gleason score (P = .02), increased tumor volume (P = .02) and positive margins (P = .04). Per cell heterogeneity of expression revealed all protein expression to be more heterogeneous in cancerous tissue (both P < .001), especially high grade (P < .01). In the first detailed analysis in cancer, a marked loss of CHD8 expression and increased BORIS/CTCF ratio indicate frequent disruption of CTCF and its effector genes in PCa. Copyright © 2014 Neoplasia Press, Inc. Published by Elsevier Inc. All rights reserved.
    Neoplasia (New York, N.Y.) 12/2014; 16(12):1018-27. DOI:10.1016/j.neo.2014.10.003 · 5.40 Impact Factor
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    • "The CHD proteins are characterized by tandem chromodomains N-terminal to their catalytic Snf2 helicase domain. There are currently 9 known members of the CHD gene family in humans (CHD1–CHD9) (Hall and Georgel, 2007; Marfella and Imbalzano, 2007), two of which (CHD3 and CHD4) have been shown to participate in multiprotein complexes responsible for chromatin remodeling (Hong et al., 2005). The nucleosome remodeling and histone deacetylation (NuRD) complex (originally known as Mi2 in Drosophila) is a large complex that consists of at least seven proteins, but the key functional protein in these complexes is either Mi- 2a or Mi-2b (now known as CHD3 and CHD4, respectively). "
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    ABSTRACT: Haploid spermatids undergo extensive cellular, molecular and morphological changes to form spermatozoa during spermiogenesis. Abnormalities in these steps can lead to serious male fertility problems, from oligospermia to complete azoospermia. CHD5 is a chromatin-remodeling nuclear protein expressed almost exclusively in the brain and testis. Male Chd5 knockout (KO) mice have deregulated spermatogenesis, characterized by immature sloughing of spermatids, spermiation failure, disorganization of the spermatogenic cycle and abnormal head morphology in elongating spermatids. This results in the inappropriate placement and juxtaposition of germ cell types within the epithelium. Sperm that did enter the epididymis displayed irregular shaped sperm heads, and retained cytoplasmic components. These sperm also stained positively for acidic aniline, indicating improper removal of histones and lack of proper chromatin condensation. Electron microscopy showed that spermatids in the seminiferous tubules of Chd5 KO mice have extensive nuclear deformation, with irregular shaped heads of elongated spermatids, and lack the progression of chromatin condensation in an anterior-to-posterior direction. However, the mRNA expression levels of other important genes controlling spermatogenesis were not affected. Chd5 KO mice also showed decreased H4 hyperacetylation beginning at stage IX, step 9, which is vital for the histone-transition protein replacement in spermiogenesis. Our data indicate that CHD5 is required for normal spermiogenesis, especially for spermatid chromatin condensation.
    Mechanisms of development 02/2014; 131:35-46. DOI:10.1016/j.mod.2013.10.005 · 2.24 Impact Factor
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    • "Because TFIID and SAGA share certain core subunits, we employed a " unique " average NSAF to identify if each complex was definitively present. For cases in which unique subunit coverage of closely related complexes was too low, we relied on shared subunits or related family members to derive a score for the family of complexes (i.e., the SET1a/b and MLL1–4 complexes, and the CHD family of proteins) (Nagy et al., 2007, Eissenberg et al., 2010, Marfella et al., 2007). Figure 1B lists the activator inducibility and rank abundance of the captured PICs. "
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    ABSTRACT: A key feature of RNA polymerase II (Pol II) preinitiation complexes (PICs) is their ability to coordinate transcription initiation with chromatin modification and remodeling. To understand how this coordination is achieved, we employed extensive proteomic and mechanistic analyses to study the composition and assembly of PICs in HeLa cell and mouse embryonic stem cell (ESC) nuclear extracts. Strikingly, most of the machinery that is necessary for transcription initiation on chromatin is part of the PIC. The PIC is nearly identical between ESCs and HeLa cells and contains two major coactivator complexes: Mediator and SAGA. Genome-wide analysis of Mediator reveals that it has a close correlation with Pol II, TATA-binding protein, and messenger RNA levels and thus may play a major role in PIC assembly. Moreover, Mediator coordinates assembly of the Pol II initiation factors and chromatin machinery into a PIC in vitro, whereas SAGA acts after PIC assembly to allow transcription on chromatin.
    Cell Reports 11/2012; 2(5). DOI:10.1016/j.celrep.2012.10.019 · 7.21 Impact Factor
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