Article

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

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.

Download full-text

Full-text

Available from: Anthony N Imbalzano, Feb 27, 2014
  • Source
    • "The first CHD gene, CHD1, was identified in a search for Ig promoter binding proteins (Delmas et al., 1993;Woodage et al., 1997) At least nine other members have been characterized to date with varying patterns of expression in timing and localization. The CHD family is a structurally diverse group comprised of three main subfamilies categorized by the presence of certain functional domains (Marfella and Imbalzano, 2007). CHD1 and CHD2 proteins contain DNA binding domains near the C-terminus that are thought to recognize AT rich motifs. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Autism Spectrum Disorder (ASD) is a common neurodevelopmental disorder with a strong but complex genetic component. Recent family based exome-sequencing strategies have identified recurrent de novo mutations at specific genes, providing strong evidence for ASD risk, but also highlighting the extreme genetic heterogeneity of the disorder. However, disruptions in these genes converge on key molecular pathways early in development. In particular, functional enrichment analyses have found that there is a bias toward genes involved in transcriptional regulation, such as chromatin modifiers. Here we review recent genetic, animal model, co-expression network, and functional genomics studies relating to the high confidence ASD risk gene, CHD8. CHD8, a chromatin remodeling factor, may serve as a "master regulator" of a common ASD etiology. Individuals with a CHD8 mutation show an ASD subtype that includes similar physical characteristics, such as macrocephaly and prolonged GI problems including recurrent constipation. Similarly, animal models of CHD8 disruption exhibit enlarged head circumference and reduced gut motility phenotypes. Systems biology approaches suggest CHD8 and other candidate ASD risk genes are enriched during mid-fetal development, which may represent a critical time window in ASD etiology. Transcription and CHD8 binding site profiles from cell and primary tissue models of early development indicate that CHD8 may also positively regulate other candidate ASD risk genes through both direct and indirect means. However, continued study is needed to elucidate the mechanism of regulation as well as identify which CHD8 targets are most relevant to ASD risk. Overall, these initial studies suggest the potential for common ASD etiologies and the development of personalized treatments in the future.
    Full-text · Article · Dec 2015 · Frontiers in Neuroscience
  • Source
    • "Nine human CHD proteins have been identified several of which have been linked to various conditions including dermatomyositis, neuroblastoma, and CHARGE syndrome (MARFELLA and IMBALZANO 2007). Loss of human CHD1 is linked to prostate cancer (HUANG et al. 2011; LIU et al. 2011), and mouse Chd1 is required for maintenance of stem cell pluripotency (GASPAR-MAIA et al. 2009) and early embryogenesis (SUZUKI et al. 2015). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The conserved chromatin remodeling and assembly factor CHD1 (chromodomains, helicase, DNA-binding domain) is present at active genes where it participates in histone turnover and recycling during transcription. In order to gain a more complete understanding of the mechanism of action of CHD1 during development we created a novel genetic assay in Drosophila melanogaster to evaluate potential functional interactions between CHD1 and other chromatin factors. We found that over-expression of the CHD1 results in defects in wing development and utilized this fully penetrant and reliable phenotype to conduct a small-scale RNAi-based candidate screen to identify genes that functionally interact with chd1 in vivo. Our results indicate that CHD1 may act in opposition to other remodeling factors, including INO80, and that the recruitment of CHD1 to active genes by RTF1 is conserved in flies.
    Preview · Article · Nov 2015 · G3-Genes Genomes Genetics
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    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.
    Full-text · Article · Dec 2014 · Neoplasia (New York, N.Y.)
Show more