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: 3.68). 06/2007; 618(1-2):30-40. DOI: 10.1016/j.mrfmmm.2006.07.012
Source: PubMed


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 · 4.25 Impact Factor
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    • "They are grouped into distinct subfamilies based on the presence of additional domains. The chromodomain-helicase-DNA-binding (CHD) family of nucleosome remodelers comprises nine proteins and is characterised by the presence of two chromodomains [3]–[5]. Three CHD proteins (CHD3, CHD4 and CHD5) share a similar domain structure that includes tandem PHD finger and chromo-domains (Fig. 1A). "
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    ABSTRACT: ATP-dependent nucleosome remodelers of the CHD family play important roles in chromatin regulation during development and differentiation. The ubiquitously expressed CHD3 and CHD4 proteins are essential for stem cell function and serve to orchestrate gene expression in different developmental settings. By contrast, the closely related CHD5 is predominantly expressed in neural tissue and its role is believed to be restricted to neural differentiation. Indeed, loss of CHD5 contributes to neuroblastoma. In this study, we first demonstrate that CHD5 is a nucleosome-stimulated ATPase. We then compare CHD3/4 and CHD5 expression in mouse brain and show that CHD5 expression is restricted to a subset of cortical and hippocampal neurons whereas CHD3/4 expression is more widespread. We also uncover high levels of CHD5 expression in testis. CHD5 is transiently expressed in differentiating germ cells. Expression is first detected in nuclei of post-meiotic round spermatids, reaches a maximum in stage VIII spermatids and then falls to undetectable levels in stage IX spermatids. Surprisingly, CHD3/4 and CHD5 show complementary expression patterns during spermatogenesis with CHD3/4 levels progressively decreasing as CHD5 expression increases. In spermatocytes, CHD3/4 localizes to the pseudoautosomal region, the X centromeric region and then spreads into the XY body chromatin. In postmeiotic cells, CHD5 colocalises with macroH2A1.2 in association with centromeres and part of the Y chromosome. The subnuclear localisations of CHD4 and CHD5 suggest specific roles in regulation of sex chromosome chromatin and pericentromeric chromatin structure prior to the histone-protamine switch.
    PLoS ONE 05/2014; 9(5):e98203. DOI:10.1371/journal.pone.0098203 · 3.23 Impact Factor
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    • "(2) CHD3 and CHD4 contain a pair of plant homeodomain zinc finger domains in their N-terminal regions and lack a DNA binding domain. (3) CHD5 to CHD9, which contain diverse additional functional domains such as the BRK (Brahma and Kismet) domain, SANT-like (switching-defective protein 3, adaptor 2, nuclear receptor corepressor, transcription factor IIIB) domain, CR domain and DNA binding domain [1,5]. "
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    ABSTRACT: The chromodomain helicase DNA binding domain (CHD) proteins modulate gene expression via their ability to remodel chromatin structure and influence histone acetylation. Recent studies have shown that CHD2 protein plays a critical role in embryonic development, tumor suppression and survival. Like other genes encoding members of the CHD family, pathogenic mutations in the CHD2 gene are expected to be implicated in human disease. In fact, there is emerging evidence suggesting that CHD2 might contribute to a broad spectrum of neurodevelopmental disorders. Despite growing evidence, a description of the full phenotypic spectrum of this condition is lacking. We conducted a multicentre study to identify and characterise the clinical features associated with haploinsufficiency of CHD2. Patients with deletions of this gene were identified from among broadly ascertained clinical cohorts undergoing genomic microarray analysis for developmental delay, congenital anomalies and/or autism spectrum disorder. Detailed clinical assessments by clinical geneticists showed recurrent clinical symptoms, including developmental delay, intellectual disability, epilepsy, behavioural problems and autism-like features without characteristic facial gestalt or brain malformations observed on magnetic resonance imaging scans. Parental analysis showed that the deletions affecting CHD2 were de novo in all four patients, and analysis of high-resolution microarray data derived from 26,826 unaffected controls showed no deletions of this gene. The results of this study, in addition to our review of the literature, support a causative role of CHD2 haploinsufficiency in developmental delay, intellectual disability, epilepsy and behavioural problems, with phenotypic variability between individuals.
    Journal of Neurodevelopmental Disorders 04/2014; 6(1):9. DOI:10.1186/1866-1955-6-9 · 3.27 Impact Factor
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