CHD6 (chromodomain helicase DNA binding protein 6)

2014-08-01   Melissa Lathrop , C Harker Rhodes , Steve Fiering 

Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA




CHD6 is a chromatin remodeling protein characterized to play a role in transcriptional repression of genes and viruses. It occurs in a nuclear location as a component of a larger complex which associates with RNA Pol II. Mutations in CHD6 are associated with motor coordination defects, and development of cancers following substitutions and translocations.


Atlas Image
CHD6 is a located on chromosome 20q12 in humans. The transcript contains 38 exons. Exons are indicated relative to size in red, 5 and 3 untranslated regions are indicated in blue. Exon number is indicated below graphic. Position of the gene on the chromosome and the location of the centromere and q terminus are indicated (adapted from the NCBI graphics viewer).


The CHD6 gene is encoded by 38 exons spanning 216394 bp. In addition to the full length transcript there are 5 predicted but not specifically reported splice variants of human CHD6. The CHD6 cDNA sequence spans 10826 bp, with a 5 untranslated region of 179 bp, an open reading frame of 8148 bp, and a 3 untranslated region of 2492 bp (NCBI: NM_032221.4) (Schuster and Stöger, 2002).


CHD6 mRNA is found in all tissues examined, with the greatest levels found on reproductive tissues, digestive tissues, brain, bone marrow, muscle, lymph node, and spleen (EMBL-EBI: E-MTAB-1733).


CHD6 in humans has no identified pseudogene.


Atlas Image
CHD6 protein functional domains. Chromodomains are highlighted in purple, the highly conserved SNF2-like ATPase region is indicated in light blue, and the DNA binding domain (green oval) contains BRK binding sights, indicated by the red diamonds.


CHD6 is a member of the very homologous SNF2 superfamily of chromatin remodeling enzymes (SWI2/SNF2, ISWI, and CHD enzyme families). These enzymes all contain a highly conserved HELICc DEAD-like helicase/ATPase with seven conserved catalytic regions (Brown et al., 2007; Marfella and Imbalzano, 2007). The nine CHD family members all contain n-terminal chromodomains and the HELICc ATPase/helicase region, and are split into three subfamilies, distinguished by the additional functional domains in each (Marfella and Imbalzano, 2007; Stanley et al., 2013). CHD6 contains a DNA binding region in its c-terminal region with conserved BRK domains (Schuster and Stöger, 2002). CHD6 is localized to the nucleus and is found in large multi-protein chromatin remodeling complexes, including the Nrf2 transcription factor (Nioi et al., 2005). Additionally, CHD6 is a DNA dependent ATPase. CHD6 protein is expected to function as a transcriptional repressor and it has been shown to be interact with RNA Pol II proteins (Lutz et al., 2006) and to be involved in the cellular repression of viral replication (Fertey et al., 2010; Alfonso et al., 2011; Alfonso et al., 2013). Size: 2715 amino acids; 305412 Da.


CHD6 protein is expressed in all tissues assayed including, monocytes, lymphocytes, kidney, liver, lung, colon, bone, brain, ovary, prostate, cervix, and breast (Data sourced from MOPED, PaxDb, and MaxQB, by Version: 3.12.142 28 July 2014). Low dose radiation induces CHD6 expression in the lymphoblastoid cell line AHH-1, and both A549 and HeLa cell lines (Wang et al., 2006).




Chromatin remodeling, transcription co-factor binding, suppression of gene expression.


CHD6 has homologues in chimpanzee, Rhesus monkey, dog, cow, mouse, rat, chicken, zebrafish, and frog.



There have been no reports of naturally occurring homozygous inactivation of CHD6. Mutations have been identified in several types of cancer, however, no nonsense or frameshift mutations exclusive to CHD6 have been associated with cancer to date (Cosmic database). Haploinsufficiency in CHD6 has been reported in miscarriage and mental retardation (Yamada et al., 2010) and mutation of the ATPase region in mice resulted in an ataxia phenotype (Lathrop et al., 2010).

Implicated in

Entity name
The presence of a fusion gene between LMBRD1 and CHD6 was identified in a case report of AML. Development of AML from an acute MDS/MPD diagnosis occurred over two years. FISH mapping of increasingly specific bacterial artificial chromosomes was used to identify the breakpoints of this AML between exons 1 and 2 of CHD6 (Douet-Guilbert et al., 2014).
Hybrid gene
Fusion gene between LMBRD1-CHD6 (6;20)(q13;q12).
Chromosome 20q12 is a common breakpoint associated with the development of MPD/MDS, however with the increased specificity of chromosome mapping techniques the frequency of the CHD6 gene specifically mutated in this disease is still being more precisely determined (Huh et al., 2010; Padhi et al., 2013).
Entity name
Colorectal cancer
CHD6 has been implicated in two studies using genome wide analysis of colorectal cancer cell lines. A comparison between tumor cell lines and primary tumors found that cell lines accurately reflect the diversity of mutations associated with primary tumor samples (Mouradov et al., 2014). Additionally this study determined that mutations in chromatin state regulators (including CHD6) are commonly found in colorectal cancer. Further research examined the copy number variation (CNV) found between colorectal cancer and normal tissue samples (Ali Hassan et al., 2014). Significant alterations in CNV were observed on chromosomes 8, 13, and 20. The gain of copies on chromosome 20q12 was the most significant finding, occurring in 45% of tumor tissues examined, specifically over a 2445 kbp region containing eight genes that include PTPRT, TOP1, and CHD6 (Ali Hassan et al., 2014).
Entity name
Bladder transitional cell carcinoma (TCC)
Analysis of multiple TCC tissues identified a group of chromatin remodeling enzyme genes with mutations occurring in 59% of patients. CHD6 was found mutated in multiple lines examined, however, only in one line was the mutation exclusive to CHD6. Linked mutation of CHD6 and two other genes, ANK2 or LRP2 was found to correlate with the development of TCC (Gui et al., 2011).
Entity name
Various cancers (malignant melanoma, glioma, cervical cancer, lung, urinary tract, large intestine, and others)
Whole genome analysis of tumor tissues and culture cell lines have identified point mutations within CHD6. These mutations and copy number variations occur at low frequencies and are often not likely pathologically associated with the development of the cancers. The alterations have been found in the following tissues: malignant melanoma (5 substitution mutations: NCBI ClinVar Database, last update 04-24-2014), multiple tumor tissue sources identifying 283 mutations in haematopoietic and lymphoid (0.23% of tested samples), central nervous system (0.74%), cervix (14.3%), endometrium (8.5%), prostate, urinary tract (14.3%), ovary, breast, lung (7.0%), stomach (6.4%), skin, kidney, large intestine (10.6%), liver, oesophagus, and pancreas. The bulk of mutations are composed of nonsense substitution: 7.42%, missense substitution: 68.90%, synonymous substitution: 27.92%, deletion frameshift: 2.12% (COSMIC Database, v69). This database further identified copynumber variants in the following tissues; haematopoietic and lymphoid, central nervous system, breast, lung, endometrium, kidney, large intestine, lung, ovary, and pancreas tumor tissues, with gain of copy number, more common than loss of copy number (COSMIC Database, v69).
Entity name
Influenza/human papillomavirus
CHD6 has been identified as playing a role in the repression of influenza A infections. It associates with viral ribonuclear proteins in infected cells (Alfonso et al., 2011). Loss of CHD6 by siRNA silencing results in an increased viral replication, while in lungs of infected mice, CHD6 is degraded upon infection and exposure to the three subunits of the viral polymerase (Alfonso et al., 2013). Recent reports also indicate that CHD6 interacts with human papillomavirus proteins, binding and repressing the expression of oncogenes (Fertey et al., 2010). This suggests that CHD6 plays a role in gene suppression and is important in the response to viral infection.
Entity name
Mutations in CHD6 that affect functional subunits are linked to the development of an ataxic phenotype. The deletion of the ATPase region of CHD6 in a mouse model resulted in deficiencies in coordinated movement, which did not progress over time (Lathrop et al., 2010). Additionally, a recent study utilizing genome wide analysis of genes associate with coordination defects in ADHD identified CHD6 as one of the most relevant target genes (Fliers et al., 2012).


Pubmed IDLast YearTitleAuthors
218996942011CHD6 chromatin remodeler is a negative modulator of influenza virus replication that relocates to inactive chromatin upon infection.Alfonso R et al
234086152013CHD6, a cellular repressor of influenza virus replication, is degraded in human alveolar epithelial cells and mice lungs during infection.Alfonso R et al
246949932014Integrated analysis of copy number variation and genome-wide expression profiling in colorectal cancer tissues.Ali Hassan NZ et al
177135802007How many remodelers does it take to make a brain? Diverse and cooperative roles of ATP-dependent chromatin-remodeling complexes in development.Brown E et al
248443652015A novel translocation (6;20)(q13;q12) in acute myeloid leukemia likely results in LMBRD1-CHD6 fusion.Douet-Guilbert N et al
206311452010Interaction of the papillomavirus E8--E2C protein with the cellular CHD6 protein contributes to transcriptional repression.Fertey J et al
214736682012Genome-wide association study of motor coordination problems in ADHD identifies genes for brain and muscle function.Fliers EA et al
218222682011Frequent mutations of chromatin remodeling genes in transitional cell carcinoma of the bladder.Gui Y et al
200950392010Characterization of chromosome arm 20q abnormalities in myeloid malignancies using genome-wide single nucleotide polymorphism array analysis.Huh J et al
201118662010Deletion of the Chd6 exon 12 affects motor coordination.Lathrop MJ et al
170279772006CHD6 is a DNA-dependent ATPase and localizes at nuclear sites of mRNA synthesis.Lutz T et al
173506552007The Chd family of chromatin remodelers.Marfella CG et al
247554712014Colorectal cancer cell lines are representative models of the main molecular subtypes of primary cancer.Mouradov D et al
163145132005The carboxy-terminal Neh3 domain of Nrf2 is required for transcriptional activation.Nioi P et al
240680642013Isolated deletion of the long arm of chromosome 20 [del(20q12)] in myelodysplastic syndrome: a case report and literature review.Padhi S et al
118895612002CHD5 defines a new subfamily of chromodomain-SWI2/SNF2-like helicases.Schuster EF et al
239544492013CHD chromatin remodelling enzymes and the DNA damage response.Stanley FK et al
166387152006Identification of differentially transcribed genes in human lymphoblastoid cells irradiated with 0.5 Gy of gamma-ray and the involvement of low dose radiation inducible CHD6 gene in cell proliferation and radiosensitivity.Wang HP et al
210864932010Characterization of a de novo balanced t(4;20)(q33;q12) translocation in a patient with mental retardation.Yamada K et al

Other Information

Locus ID:

NCBI: 84181
MIM: 616114
HGNC: 19057
Ensembl: ENSG00000124177


dbSNP: 84181
ClinVar: 84181
TCGA: ENSG00000124177


Gene IDTranscript IDUniprot

Expression (GTEx)



Pubmed IDYearTitleCitations
203796142010Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.62
118895612002CHD5 defines a new subfamily of chromodomain-SWI2/SNF2-like helicases.20
170279772006CHD6 is a DNA-dependent ATPase and localizes at nuclear sites of mRNA synthesis.19
218996942011CHD6 chromatin remodeler is a negative modulator of influenza virus replication that relocates to inactive chromatin upon infection.19
285334322017The ATP-dependent chromatin remodeling enzymes CHD6, CHD7, and CHD8 exhibit distinct nucleosome binding and remodeling activities.16
206311452010Interaction of the papillomavirus E8--E2C protein with the cellular CHD6 protein contributes to transcriptional repression.9
234086152013CHD6, a cellular repressor of influenza virus replication, is degraded in human alveolar epithelial cells and mice lungs during infection.6
256318772015CHD6 regulates the topological arrangement of the CFTR locus.4
256318772015CHD6 regulates the topological arrangement of the CFTR locus.4
306515622019The CHD6 chromatin remodeler is an oxidative DNA damage response factor.2


Melissa Lathrop ; C Harker Rhodes ; Steve Fiering

CHD6 (chromodomain helicase DNA binding protein 6)

Atlas Genet Cytogenet Oncol Haematol. 2014-08-01

Online version: