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Functional Insights Into Chromatin Remodelling from Studies On Special Issue: Human Genetics Review Functional Insights into Chromatin Remodelling from Studies on CHARGE Syndrome 1, 2 M. Albert Basson, * and Conny van Ravenswaaij-Arts CHARGE syndrome is a rare genetic syndrome characterised by a unique com- Trends bination of multiple organ anomalies. Dominant loss-of-function mutations in the The expressivity and penetrance of gene encoding chromodomain helicase DNA binding protein 7 (CHD7), which is CHARGE phenotypes show little cor- relation with the CHD7 genotype. an ATP-dependent chromatin remodeller, have been identified as the cause of CHARGE syndrome. Here, we review recent work aimed at understanding the The hypothesis that mutations or poly- morphisms in other genes modify dis- mechanism of CHD7 function in normal and pathological states, highlighting ease phenotypes in humans remains in vivo results from biochemical and studies. The emerging picture from this work unproven. suggests that the mechanisms by which CHD7 fine-tunes gene expression are CHARGE-associated CHD7 mutations context specific, consistent with the pleiotropic nature of CHARGE syndrome. can affect its nucleosome remodelling activity in vitro. Molecular Origins of CHARGE Syndrome Advances in genomics over the past few years have led to impressive achievements in the The role of CHD7 in regulating nucleo- some positioning in vivo and the effects identification of mutations responsible for rare genetic diseases, especially those with simple, of this activity on gene expression monogenetic aetiologies [1]. The identification of the genetic cause of a disease represents a require further study. major milestone because biochemical and gene targeting approaches can then be used to explore the biological functions of the gene in question and investigate the molecular mecha- CHD7 pleiotropy may result from its interactions with cell type-specific tran- nisms that underlie the disease. Typically, the insights gained from these studies have wide- scription factors. reaching implications by revealing fundamental biological principles that control development and homeostasis. CHARGE syndrome (MIM 214800) is a good example of such a case. This CHD7 recruitment to cell type-specific syndrome is diagnosed in 1/10 000 live births and is characterised by dysmorphic features and enhancers may underlie context-spe- cific roles. congenital anomalies in multiple organs. The development of the nervous system (especially cranial nerves), ears and vestibular organs, eyes, heart, urogenital, and endocrine systems can be affected and growth retardation is often observed. The presence and severity of these anomalies show remarkable variation between patients. 1 King's College London, Department In 2004, shortly before the next-generation sequencing era, mutations in the CHD7 gene (MIM of Craniofacial Development and Stem Cell Biology and MRC Centre for 608892) were identified in patients with CHARGE syndrome [2]. CHD7 encodes a chromatin- Developmental Neurobiology, Floor remodelling factor (CRF), which implied an epigenetic aetiology for CHARGE syndrome. CRFs 27, Guy's Hospital Tower Wing, have evolved to deal with the additional complexity and hindrance that the tight association of London, SE1 9RT, UK 2 University of Groningen, University eukaryotic DNA with histone proteins imposes on replication and transcription (Box 1). CRFs Medical Center Groningen, perform several essential functions. For instance, the clearance of nucleosomes from promoters Department of Genetics, PO Box and other regulatory elements is necessary for the recruitment of some transcription factors (TFs) 30.001, 9700RB Groningen, The Netherlands and the core transcriptional machinery, and nucleosome eviction is essential for efficient transcriptional elongation. Conversely, the maintenance of heterochromatin is an important *Correspondence: mechanism for stable gene repression. Thus, different classes of CRF can have opposing [email protected] (M.A. Basson). 600 Trends in Genetics, October 2015, Vol. 31, No. 10 http://dx.doi.org/10.1016/j.tig.2015.05.009 © 2015 Elsevier Ltd. All rights reserved. Box 1. The Concept of Chromatin Remodelling Glossary Chromatin remodelling refers to the active process of changing the structure and organisation of chromatin. Histone 22q11del syndrome: most common subunits, termed H2A, H2B, H3, and H4, that comprise the core nucleosomal particles around which DNA is wound, are microdeletion (1.5-3MB) syndrome, globular proteins with exposed N-terminal ‘tails’ that contain several amino acid residues that are accessible to modifying also known as velocardiofacial or enzymes that catalyse the covalent addition of chemical moieties. These modifications include acetylation, methylation, DiGeorge syndrome. phosphorylation, ubiquitination, and ADP ribosylation, among others [66]. The linker histone H1 is also subject to covalent Absent, small, or homeotic-like 1 modification. Histone modifications can alter the chemical properties of the nucleosome and its interaction with DNA [67]. (ASH1): a member of the trithorax The combination of histone modifications carried by a nucleosomal array on chromatin creates unique binding sites, group and a histone-lysine N- which can affect CRF recruitment to this region. The most direct and dramatic changes in chromatin structure are methyltransferase. catalysed by chromatin-remodelling enzymes. These CRFs are ATP-dependent molecular machines that can alter the Choanal atresia: anatomical position of nucleosomes on chromatin. Repositioning nucleosomes, or even evicting them completely from chromatin at obstruction of the back of the nasal a given locus, changes the accessibility of specific DNA sequences. As a consequence, TF binding sites may either passage, interfering with the ability to become available for, or be obscured from, binding by their cognate TF (Figure 2, main text). These changes may affect breathe. chromatin architecture on a larger scale if the DNA–protein interactions that are altered upon the action of CRFs are Chromodomain: protein structural involved in maintaining higher order chromatin organisation, such as those mediated by insulating factors, including domain of approximately 40–50 CTCF. amino acid residues commonly found in proteins associated with chromatin fi ATP-dependent CRFs are classi ed in three different groups: SWI/SNF, ISWI, and CHD. CRFs typically function in large, remodelling. multi-subunit protein complexes. The composition of these complexes may differ between different cell types, thereby Coloboma: an embryonic closure altering the nature of the complex, as exemplified by the BAF complex [68]. The observation that active gene promoters defect of the eye (e.g., affecting the and enhancer elements can be identified empirically by nuclease-sensitivity assays as a proxy for DNA accessibility iris and/or the retina). In CHARGE implicates CRFs in the establishment and maintenance of chromatin structure at regulatory elements. syndrome, retinal coloboma results in partial or complete loss of sight. Germline mosaicism: a situation activities and functions, and local chromatin context can determine the effects of a CRF at a where germ cells in an individual specific locus [3]. differ with respect to a specific genetic feature, usually caused by a de novo mutation in one germ cell In this review, we summarise some of the most recent studies that link CHD7 to specific progenitor during development or developmental genes and pathways. We discuss in vitro experiments that provide insights into expansion. The chance of a disease- CHD7 mechanism and highlight the significant gaps in our understanding of how CHD7 acts in causing mutation being transmitted vivo to fine-tune gene expression and control development. However, we begin with the clinical to offspring depends on the proportion of mutated germ cells. data obtained from patients and summarise our current knowledge of CHD7 mutations that H3K27me3: Lysine 27 tri-methylation cause CHARGE syndrome. of histone 3, a post-translational modification typically associated with The Phenotypic Spectrum of CHARGE Syndrome repressed regulatory regions. H3K36me3: Lysine 36 tri-methylation CHARGE syndrome is characterised by a multitude of congenital aberrations that can vary in of histone 3, a post-translational both severity and presence. The most frequent features seen in patients with a CHD7 mutation modification typically associated with are: external ear malformations (97%); cranial nerve dysfunction (99%, causing facial palsy in gene bodies undergoing active 66%); semicircular canal anomalies (94%); coloboma (81%; see Glossary); choanal atresia transcription, used as an indicator of transcriptional elongation. (55%); cleft lip and/or palate (48%); anosmia (80%); genital hypoplasia (81%); congenital heart H3K4me3: modification typically defects (76%); and tracheoesophageal anomalies (29%). In addition, severe feeding problems associated with active promoter (82%), delayed motor development milestones (99%), intellectual disability (74%), and growth regions. Imitation switch (ISWI): a class of retardation (37%) are observed [4–8] (percentages according to [8]). ATP-dependent CRFs. Kallmann syndrome: a syndrome The clinical diagnosis of CHARGE syndrome is based on major and minor diagnostic criteria characterised by hypogonadism and formulated by Blake [9], which were later refined by Verloes [10]. Major criteria are the presence anosmia (inability to smell), due to failure of gonadotropin-releasing of coloboma, choanal atresia, characteristic
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