Alternative titles; symbols
HGNC Approved Gene Symbol: CHD4
Cytogenetic location: 12p13.31 Genomic coordinates (GRCh38) : 12:6,570,082-6,607,379 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12p13.31 | Sifrim-Hitz-Weiss syndrome | 617159 | Autosomal dominant | 3 |
The CHD4 gene encodes a chromodomain-containing protein that catalyzes ATP-dependent chromatin remodeling as a core component of the nucleosome remodeling and histone deacetylase (NURD) repressor complex, which is involved in epigenetic regulation of gene transcription, DNA repair, and cell cycle progression (summary by Sifrim et al., 2016 and Weiss et al., 2016).
Approximately 20% of patients with dermatomyositis develop antibodies against nuclear antigens that are termed Mi2. Sera containing anti-Mi2 antibodies precipitate several proteins, with 1 of the most abundant migrating as a 220- to 260-kD polypeptide on SDS-polyacrylamide gels. By immunoscreening a HeLa cell cDNA expression library with sera from a patient with dermatomyositis, Seelig et al. (1995) isolated a full-length cDNA encoding CHD4, which they called Mi2-beta. Northern blot analysis of Hep-2 cell RNA detected an approximately 6.8-kb Mi2-beta transcript. The deduced 1,912-amino acid protein has a calculated molecular mass of 218 kD. Native Mi2-beta from Hep-2 cells has a molecular mass of 235 kD by SDS-PAGE. Searches of sequence databases indicated that Mi2-beta belongs to the SNF2/RAD54 family of nuclear helicases. The central portion of Mi2-beta contains the 7 motifs, including a DEAD/H box, that are characteristic of helicases. Mi2-beta also contains a putative chromatin-binding region and multiple potential nuclear targeting signals, N-glycosylation sites, N-myristoylation sites, and phosphorylation sites. Immunofluorescence studies localized the Mi2-beta protein to the nucleus. The authors concluded that Mi2-beta is a major antigen recognized by anti-Mi2 sera from patients with dermatomyositis. Studies with sera from dermatomyositis, systemic lupus erythematosus (152700), and rheumatoid arthritis (180300) patients showed that anti-Mi2-beta antibodies are predominantly found in dermatomyositis patients.
Seelig et al. (1996) noted that the Mi2-alpha (CHD3; 602120) and Mi2-beta proteins react with most or all dermatomyositis patient anti-Mi2 sera. While these proteins are distinct, they have stretches of identical sequences that could result in shared epitopes. The authors stated that Mi2-alpha and Mi2-beta contain a PHD motif, which is a zinc finger-like motif with a cys4-his-cys3 pattern and which is thought to be a DNA- or RNA-binding domain.
See CHD1 (602118) for a description of this gene family.
Zhang et al. (1998) reported the isolation of a protein complex that contains both histone deacetylation and ATP-dependent nucleosome remodeling activities. The complex contained the histone deacetylases HDAC1/2, histone-binding proteins, the dermatomyositis-specific autoantigen Mi2-beta, a polypeptide related to the metastasis-associated protein-1, and a novel polypeptide of 32 kD. Patients with dermatomyositis have a high rate of malignancy. The finding that Mi2-beta exists in a complex containing histone deacetylase and nucleosome remodeling activities suggests a role for chromatin reorganization in cancer metastasis.
Zhang et al. (1999) showed that MTA2 (MTA1L1; 603947) and the 32-kD MBD3 (603573) protein are subunits of the NURD (nucleosome remodeling and histone deacetylase) complex (see MTA1; 603526). Immunoprecipitation analysis showed that MBD3 interacts with HDAC1 (601241), RBBP4 (602923), and RBBP7 (300825), but not with MI2, suggesting that MBD3 is embedded within the NURD complex. The authors found that MTA2 directs the assembly of an active histone deacetylase complex and that the association of MTA2 with the complex requires MBD3. Gel mobility shift analysis determined that both NURD and MBD3 are unable to bind to methylated DNA in the absence of MBD2 (603547). Zhang et al. (1999) proposed that NURD is involved in the transcriptional repression of methylated DNA. Wade et al. (1999) also identified MTA1, MTA1L, and MBD3 as components of the NURD complex, which they referred to as the MI2 complex.
By immunoprecipitation analysis, Shimono et al. (2005) found that MCRS1 (609504) interacted with MI2-beta, RFP (TRIM27; 602165), and UBF (UBTF; 600673). Yeast 2-hybrid screening showed that the central region of MCRS1 interacted with the ATPase/helicase region of MI2-beta and the coiled-coil region of RFP. Confocal microscopy demonstrated colocalization of MCRS1, MI2-beta, RFP, and UBF in nucleoli. Chromatin immunoprecipitation assays showed that MCRS1, MI2-beta, and RFP associated with rDNA and were involved in transactivation of ribosomal gene transcription, which could be downregulated by small interfering RNA-mediated downregulation of MCRS1, MI2-beta, and RFP. Shimono et al. (2005) concluded that MI2-beta and RFP, which are involved in transcriptional repression in the nucleus, associate with MCRS1 in the nucleolus and are involved in activation of rRNA transcription.
Ostapcuk et al. (2018) showed that ADNP (611386) interacts with the chromatin remodeler CHD4 and the chromatin architectural protein HP1 (604478) to form a stable complex, which they referred to as ChAHP. Besides mediating complex assembly, ADNP recognizes DNA motifs that specify binding of ChAHP to euchromatin. Genetic ablation of ChAHP components in mouse embryonic stem cells resulted in spontaneous differentiation concomitant with premature activation of lineage-specific genes and in a failure to differentiate towards the neuronal lineage. Molecularly, ChAHP-mediated repression is fundamentally different from canonical HP1-mediated silencing: HP1 proteins, in conjunction with histone H3 lysine-9 trimethylation (H3K9me3), are thought to assemble broad heterochromatin domains that are refractory to transcription. ChAHP-mediated repression, however, acts in a locally restricted manner by establishing inaccessible chromatin around its DNA-binding sites and does not depend on H3K9me3-modified nucleosomes. Ostapcuk et al. (2018) concluded that their results revealed that ADNP, via the recruitment of HP1 and CHD4, regulates the expression of genes that are crucial for maintaining distinct cellular states and assures accurate cell fate decisions upon external cues. Such a general role of ChAHP in governing cell fate plasticity may explain why ADNP mutations affect several organs and body functions and contribute to cancer progression. Ostapcuk et al. (2018) found that the integrity of the ChAHP complex is disrupted by nonsense mutations identified in patients with Helsmoortel-Van der Aa syndrome (615873), and this could be rescued by aminoglycosides that suppress translation termination.
Using a CRISPR screen, Lan et al. (2021) identified ZNF410 (619427) as a repressor of gamma-globin (see 142250) gene expression in HUDEP2 human erythroid cells. Depletion of ZNF410 in primary human erythroblasts elevated the gamma-globin levels. ZNF410 directly targeted the CHD4 gene in erythroid cells and repressed transcription of gamma-globin by modulating CHD4 expression. ZNF410 bound to chromatin at 2 unique, highly conserved dense site clusters near the CHD4 gene. The zinc finger domain of ZNF410 was necessary and sufficient for binding to DNA.
Using a CRISPR screen, Vinjamur et al. (2021) independently identified ZNF410 as a repressor of fetal hemoglobin (HbF) in HUDEP2 cells. They validated the finding by knockout analysis in HUDEP2 cells and primary adult erythroid precursors. ZNF410 did not bind directly to the genes encoding HbF subunit gamma-globins. Instead, ZNF410 repressed gamma-globins exclusively by binding upstream elements and transactivating CHD4. ZNF410 chromatin occupancy was solely restricted to the CHD4 locus, which contained 2 ZNF410-bound regulatory elements with 27 combined ZNF410-binding motifs. Analysis of chromatin occupancy of endogenous Zfp410 in a mouse erythroid cell line showed results similar to those observed in human erythroid precursors, indicating that ZNF410 is an evolutionarily conserved HbF repressor.
By fluorescence in situ hybridization, Seelig et al. (1995) mapped the CHD4 gene to chromosome 12p13.
Sifrim-Hitz-Weiss Syndrome
In 5 unrelated patients with Sifrim-Hitz-Weiss syndrome (SIHIWES; 617159), Sifrim et al. (2016) identified 5 different de novo heterozygous mutations in the CHD4 gene (see, e.g., 603277.0001-603277.0003). There were 4 missense mutations and 1 in-frame deletion. Functional studies of the variants and studies of patient cells were not performed. The patients were ascertained from a cohort of 518 trios in which a child had syndromic congenital heart defects who underwent exome sequencing. Statistical analysis indicated that de novo mutations in the CHD4 gene were significantly enriched in patients compared to those expected under a null mutational model (p = 2.28 x 10(-7), Bonferroni-corrected p = 0.05).
In 5 unrelated patients with SIHIWES, Weiss et al. (2016) identified 4 different de novo heterozygous missense mutations in the CHD4 gene (see, e.g., 603277.0004-603277.0006). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. Three of the mutations occurred at highly conserved residues in the C-terminal helicase domain and were predicted to disrupt the ATPase activity of CHD4.
Somatic Mutations
Le Gallo et al. (2012) used whole-exome sequencing to comprehensively search for somatic mutations in 13 primary serous endometrial tumors (see 608089), and subsequently resequenced 18 genes that were mutated in more than 1 tumor and/or were components of an enriched functional grouping from 40 additional serous tumors. Le Gallo et al. (2012) identified a high frequency of somatic mutation in the CHD4 gene (17%).
In a 3-year-old boy (patient 1) with Sifrim-Hitz-Weiss syndrome (SIHIWES; 617159), Sifrim et al. (2016) identified a de novo heterozygous c.4822G-A transition (c.4822G-A, NM_001273.3) in the CHD4 gene, resulting in a val1608-to-ile (V1608I) substitution. The mutation was found by exome sequencing. Functional studies of the variant and studies of patient cells were not performed.
In a 16.9-year-old boy (patient 2) with Sifrim-Hitz-Weiss syndrome (SIHIWES; 617159), Sifrim et al. (2016) identified a de novo heterozygous c.3203G-A transition (c.3203G-A, NM_001273.3) in the CHD4 gene, resulting in an arg1068-to-his (R1068H) substitution. Functional studies of the variant and studies of patient cells were not performed.
In an 11-year-old girl (patient 4) with Sifrim-Hitz-Weiss syndrome (SIHIWES; 617159), Sifrim et al. (2016) identified a de novo heterozygous c.2552C-A transversion (c.2552C-A, NM_001273.3) in the CHD4 gene, resulting in a ser851-to-tyr (S851Y) substitution. Functional studies of the variant and studies of patient cells were not performed.
In 2 unrelated 10-year-old boys (patients 1 and 3) with Sifrim-Hitz-Weiss syndrome (SIHIWES; 617159), Weiss et al. (2016) identified a de novo heterozygous c.3380G-A transition (c.3380G-A, NM_001273.3) in the CHD4 gene, resulting in an arg1127-to-gln (R1127Q) substitution at a highly conserved residue in the C terminal helicase domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the ExAC database. Coimmunoprecipitation studies and Western blot analysis showed that the mutant protein localized properly to the nucleus and interacted normally with HDAC1 (601241), suggesting that the mutation did not affect CHD4 complex formation. However, the substitution was predicted to disrupt ATPase activity. Patient 1 also carried a de novo heterozygous missense variant in the APOBEC1 gene (600130) that was predicted to be deleterious, and patient 3 carried several additional variants in other genes that were inherited from an unaffected parent.
In a 16-year-old girl (patient 2) with Sifrim-Hitz-Weiss syndrome (SIHIWES; 617159), Weiss et al. (2016) identified a de novo heterozygous c.3518G-T transversion (c.3518G-T, NM_001273.3) in the CHD4 gene, resulting in an arg1173-to-leu (R1173L) substitution at a highly conserved residue in the C-terminal helicase domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the ExAC database. Coimmunoprecipitation studies and Western blot analysis showed that the mutant protein localized properly to the nucleus and interacted normally with HDAC1 (601241), suggesting that the mutation does not affect CHD4 complex formation. However, the substitution was predicted to disrupt ATPase activity.
In a 5-year-old girl (patient 4) with Sifrim-Hitz-Weiss syndrome (SIHIWES; 617159), Weiss et al. (2016) identified a de novo heterozygous c.3443G-T transversion (c.3443G-T, NM_001273.3) in the CHD4 gene, resulting in a trp1148-to-leu (W1148L) substitution at a highly conserved residue in the C-terminal helicase domain. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant and studies on patient cells were not performed.
Lan, X., Ren, R., Feng, R., Ly, L. C., Lan, Y., Zhang, Z., Aboreden, N., Qin, K., Horton, J. R., Grevet, J. D., Mayuranathan, T., Abdulmalik, O., Keller, C. A., Giardine, B., Hardison, R. C., Crossley, M., Weiss, M. J., Cheng, X., Cheng, X., Shi, J., Blobel, G. A. ZNF410 uniquely activates the NuRD component CHD4 to silence fetal hemoglobin expression. Molec. Cell 81: 239-254, 2021. [PubMed: 33301730] [Full Text: https://doi.org/10.1016/j.molcel.2020.11.006]
Le Gallo, M., O'Hara, A. J., Rudd, M. L., Urick, M. E., Hansen, N. F., O'Neil, N. J., Price, J. C., Zhang, S., England, B. M., Godwin, A. K., Sgroi, D. C., NIH Intramural Sequencing Center (NISC) Comparative Sequencing Program, Hieter, P., Mullikan, J. C., Merino, M. J., Bell, D. W. Exome sequencing of serous endometrial tumors identifies recurrent somatic mutations in chromatin-remodeling and ubiquitin ligase complex genes. Nature Genet. 44: 1310-1315, 2012. [PubMed: 23104009] [Full Text: https://doi.org/10.1038/ng.2455]
Ostapcuk, V., Mohn, F., Carl, S. H., Basters, A., Hess, D., Iesmantavicius, V., Lampersberger, L., Flemr, M., Pandey, A., Thoma, N. H., Betschinger, J., Buhler, M. Activity-dependent neuroprotective protein recruits HP1 and CHD4 to control lineage-specifying genes. Nature 557: 739-743, 2018. [PubMed: 29795351] [Full Text: https://doi.org/10.1038/s41586-018-0153-8]
Seelig, H. P., Moosbrugger, I., Ehrfeld, H., Fink, T., Renz, M., Genth, E. The major dermatomyositis-specific Mi-2 autoantigen is a presumed helicase involved in transcriptional activation. Arthritis Rheum. 38: 1389-1399, 1995. [PubMed: 7575689] [Full Text: https://doi.org/10.1002/art.1780381006]
Seelig, H. P., Renz, M., Targoff, I. N., Ge, Q., Frank, M. B. Two forms of the major antigenic protein of the dermatomyositis-specific Mi-2 autoantigen. (Letter) Arthritis Rheum. 39: 1769-1771, 1996. [PubMed: 8843877] [Full Text: https://doi.org/10.1002/art.1780391029]
Shimono, K., Shimono, Y., Shimokata, K., Ishiguro, N., Takahashi, M. Microspherule protein 1, Mi-2-beta, and RET finger protein associate in the nucleolus and up-regulate ribosomal gene transcription. J. Biol. Chem. 280: 39436-39447, 2005. [PubMed: 16186106] [Full Text: https://doi.org/10.1074/jbc.M507356200]
Sifrim, A., Hitz, M.-P., Wilsdon, A., Breckpot, J., Al Turki, S. H., Thienpont, B., McRae, J., Fitzgerald, T. W., Singh, T., Swaminathan, G. J., Prigmore, E., Rajan, D., and 63 others. Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing. Nature Genet. 48: 1060-1065, 2016. [PubMed: 27479907] [Full Text: https://doi.org/10.1038/ng.3627]
Vinjamur, D. S., Yao, Q., Cole, M. A., McGuckin, C., Ren, C., Zeng, J., Hossain, M., Luk, K., Wolfe, S. A., Pinello, L., Bauer, D. E. ZNF410 represses fetal globin by singular control of CHD4. Nature Genet. 53: 719-728, 2021. [PubMed: 33859416] [Full Text: https://doi.org/10.1038/s41588-021-00843-w]
Wade, P. A., Gegonne, A., Jones, P. L., Ballestar, E., Aubry, F., Wolffe, A. P. Mi-2 complex couples DNA methylation to chromatin remodelling and histone deacetylation. Nature Genet. 23: 62-66, 1999. [PubMed: 10471500] [Full Text: https://doi.org/10.1038/12664]
Weiss, K., Terhal, P. A., Cohen, L., Bruccoleri, M., Irving, M., Martinez, A. F., Rosenfeld, J. A., Machol, K., Yang, Y., Liu, P., Walkiewicz, M., Beuten, J., and 16 others. De novo mutations in CHD4, an ATP-dependent chromatin remodeler gene, cause an intellectual disability syndrome with distinctive dysmorphisms. Am. J. Hum. Genet. 99: 934-941, 2016. [PubMed: 27616479] [Full Text: https://doi.org/10.1016/j.ajhg.2016.08.001]
Zhang, Y., LeRoy, G., Seelig, H.-P., Lane, W. S., Reinberg, D. The dermatomyositis-specific autoantigen Mi2 is a component of a complex containing histone deacetylase and nucleosome remodeling activities. Cell 95: 279-289, 1998. [PubMed: 9790534] [Full Text: https://doi.org/10.1016/s0092-8674(00)81758-4]
Zhang, Y., Ng, H.-H., Erdjument-Bromage, H., Tempst, P., Bird, A., Reinberg, D. Analysis of the NuRD subunits reveals a histone deacetylase core complex and a connection with DNA methylation. Genes Dev. 13: 1924-1935, 1999. [PubMed: 10444591] [Full Text: https://doi.org/10.1101/gad.13.15.1924]