Human CHD2 Is a Chromatin Assembly ATPase Regulated by Its Chromo- and DNA-binding Domains

Liu, Jessica C.; Ferreira, Catarina G.; Yusufzai, Timur

doi:10.1074/jbc.m114.609156

Cited by 40 publications

(58 citation statements)

References 45 publications

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“…As a result it is somewhat surprising that the area of contact between the chromodomains and DNABD is so small. It is possible that additional regions of Chd1 including the Nterminus that is not resolved in the density map also contribute to this interaction as suggested by previous studies of Chd1 proteins (Liu et al, 2015;Zhou et al, 2018) (Sundaramoorthy et al, 2017).…”

Section: Resultsmentioning

confidence: 90%

Structure of the chromatin remodelling enzyme Chd1 bound to a ubiquitinylated nucleosome

Sundaramoorthy

Hughes

Mkami

et al. 2018

Preprint

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ATP-dependent chromatin remodelling proteins represent a diverse family of proteins that share ATPase domains that are adapted to regulate protein-DNA interactions. Here we present structures of the yeast Chd1 protein engaged with nucleosomes in the presence of the transition state mimic ADP-beryllium fluoride. The path of DNA strands through the ATPase domains indicates the presence of contacts conserved with single strand translocases and additional contacts with both strands that are unique to Snf2 related proteins. The structure provides connectivity between rearrangement of ATPase lobes to a closed, nucleotide bound state and the sensing of linker DNA. Two turns of linker DNA are prised off the surface of the histone octamer as a result of Chd1 binding, and both the histone H3 tail and ubiquitin conjugated to lysine 120 are re-orientated towards the unravelled DNA. This indicates how changes to nucleosome structure can alter the way in which histone epitopes are presented.

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Section: Resultsmentioning

confidence: 90%

Structure of the chromatin remodelling enzyme Chd1 bound to a ubiquitinylated nucleosome

Sundaramoorthy

Hughes

Mkami

et al. 2018

Preprint

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“…Recent studies have confirmed that the C-terminal portion of CHD2 is a functional DBD that displays selectivity for double-stranded DNA and is necessary for the stimulation of the ATPase and chromatin remodeling activities of this protein. 47 The aberrant nuclear distribution of CHD2 L1270F , together with the loss of association of this mutant with active gene transcription, suggests a functional impact of CHD2 mutations, including truncations, in CLL, likely through transcriptional activation of CLLrelevant genes. In fact, transcriptomic studies and GSEA highlighted significant core enrichment for functional pathways associated with distinct chromatin remodeling processes, from DNA unwinding to the regulation of the acetylation and phosphorylation of histone H3 by the anaphase promoting complex.…”

Section: Discussionmentioning

confidence: 99%

Mutations in CHD2 cause defective association with active chromatin in chronic lymphocytic leukemia

Rodrı́guez

Bretones

Quesada

et al. 2015

Blood

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Key Points• Somatic mutations alter nuclear distribution and association of CHD2 with actively transcribed genes in CLL.• CHD2 is the most frequently mutated CLL driver in the IGHV-mutated prognostic subgroup.Great progress has recently been achieved in the understanding of the genomic alterations driving chronic lymphocytic leukemia (CLL). Nevertheless, the specific molecular mechanisms governing chromatin remodeling in CLL are unknown. Here we report the genetic and functional characterization of somatic mutations affecting the chromatin remodeler CHD2, one of the most frequently mutated genes in CLL (5.3%) and in monoclonal B lymphocytosis (MBL, 7%), a B-cell expansion that can evolve to CLL. Most of the mutations affecting CHD2, identified by whole-exome sequencing of 456 CLL and 43 MBL patients, are either truncating or affect conserved residues in functional domains, thus supporting a putative role for CHD2 as a tumor suppressor gene. CHD2 mutants show altered nuclear distribution, and a chromodomain helicase DNA binding protein 2 (CHD2) mutant affected in its DNA-binding domain exhibits defective association with active chromatin. Clinicobiological analyses show that most CLL patients carrying CHD2 mutations also present mutated immunoglobulin heavy chain variable region genes (IGHVs), being the most frequently mutated gene in this prognostic subgroup. This is the first study providing functional evidence supporting CHD2 as a cancer driver and opens the way to further studies of the role of this chromatin remodeler in CLL. (Blood. 2015;126(2):195-202) IntroductionChronic lymphocytic leukemia (CLL) is the most prevalent B-cell neoplasm in Western adults. CLL shows a remarkably heterogeneous course, with some patients presenting an indolent disease and normal life span, whereas others suffer from a dismal prognosis. [1][2][3] In general, disease outcome correlates with the immunoglobulin heavy chain variable region genes (IGHV) mutational status of tumor lymphocytes, 4,5 but also with other biological features including chromosomal aberrations and the expression of CLL-specific biomarkers. [5][6][7][8] Recently, whole-genome sequencing-based reports have uncovered NOTCH1, MYD88, and XPO1 as recurrently mutated CLL drivers.9 Additionally, whole-exome sequencing approaches have identified the splicing factor SF3B1 10-13 and the shelterin complex member POT1 14 as CLL drivers associated with unfavorable prognosis. Also, mutations in sucrose isomaltase have been proposed to play a role in the CLL leukemogenic metabolic switch. 15 Moreover, clonal evolution events in CLL have been delineated, pointing to the presence of subclonal driver mutations as a relevant prognostic factor in this disease.16 Notably, mutations in many of the previously described driver genes, as well as in BRAF, EGR2, and NFKBIE, can be detected in pluripotent hematopoietic progenitor cells, indicating that founding CLL mutations appear as very early evolutionary events.17 These genomic studies have been extended by comprehensive transc...

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“…The ATP‐dependent activity of CHD2 leads to assembly of chromatin into periodic nucleosome arrays by deposition of various histone proteins, thereby modifying the expression and structure of target sites (Liu et al. ; Luijsterburg et al. ).…”

Section: Introductionmentioning

confidence: 99%

Autism‐linked CHD gene expression patterns during development predict multi‐organ disease phenotypes

2018

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Recent large‐scale exome sequencing studies have identified mutations in several members of the CHD (Chromodomain Helicase DNA‐binding protein) gene family in neurodevelopmental disorders. Mutations in the CHD2 gene have been linked to developmental delay, intellectual disability, autism and seizures, CHD8 mutations to autism and intellectual disability, whereas haploinsufficiency of CHD7 is associated with executive dysfunction and intellectual disability. In addition to these neurodevelopmental features, a wide range of other developmental defects are associated with mutants of these genes, especially with regards to CHD7 haploinsufficiency, which is the primary cause of CHARGE syndrome. Whilst the developmental expression of CHD7 has been reported previously, limited information on the expression of CHD2 and CHD8 during development is available. Here, we compare the expression patterns of all three genes during mouse development directly. We find high, widespread expression of these genes at early stages of development that gradually becomes restricted during later developmental stages. Chd2 and Chd8 are widely expressed in the developing central nervous system (CNS) at all stages of development, with moderate expression remaining in the neocortex, hippocampus, olfactory bulb and cerebellum of the postnatal brain. Similarly, Chd7 expression is seen throughout the CNS during late embryogenesis and early postnatal development, with strong enrichment in the cerebellum, but displays low expression in the cortex and neurogenic niches in early life. In addition to expression in the brain, novel sites of Chd2 and Chd8 expression are reported. These findings suggest additional roles for these genes in organogenesis and predict that mutation of these genes may predispose individuals to a range of other, non‐neurological developmental defects.

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Human CHD2 Is a Chromatin Assembly ATPase Regulated by Its Chromo- and DNA-binding Domains

Cited by 40 publications

References 45 publications

Structure of the chromatin remodelling enzyme Chd1 bound to a ubiquitinylated nucleosome

Structure of the chromatin remodelling enzyme Chd1 bound to a ubiquitinylated nucleosome

Mutations in CHD2 cause defective association with active chromatin in chronic lymphocytic leukemia

Autism‐linked CHD gene expression patterns during development predict multi‐organ disease phenotypes

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