CHD8

CHD8
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2CKA, 2DL6
Identifiers
Aliases	CHD8 , AUTS18, HELSNF1, chromodomain helicase DNA binding protein 8, IDDAM
External IDs	OMIM: 610528; MGI: 1915022; HomoloGene: 72405; GeneCards: CHD8; OMA:CHD8 - orthologs
Gene location (Human) Chr. Chromosome 14 (human) [1] Band 14q11.2 Start 21,385,194 bp [1] End 21,456,126 bp [1]
Gene location (Mouse) Chr. Chromosome 14 (mouse) [2] Band 14|14 C2 Start 52,435,608 bp [2] End 52,495,237 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in sural nerve ventricular zone right hemisphere of cerebellum granulocyte ganglionic eminence skin of leg skin of abdomen epithelium of colon anterior pituitary spleen Top expressed in tail of embryo genital tubercle Rostral migratory stream zygote internal carotid artery ventricular zone secondary oocyte external carotid artery fossa Ileal epithelium More reference expression data BioGPS More reference expression data
Gene ontology Molecular function DNA binding nucleotide binding ATP-dependent activity, acting on DNA helicase activity chromatin binding methylated histone binding hydrolase activity, acting on acid anhydrides DNA helicase activity protein binding hydrolase activity ATP binding p53 binding beta-catenin binding histone binding armadillo repeat domain binding Cellular component nucleoplasm MLL1 complex nucleus protein-containing complex Biological process regulation of transcription, DNA-templated negative regulation of transcription by RNA polymerase II Wnt signaling pathway transcription, DNA-templated positive regulation of transcription, DNA-templated brain development digestive tract development positive regulation of transcription by RNA polymerase III negative regulation of canonical Wnt signaling pathway positive regulation of transcription by RNA polymerase II DNA duplex unwinding chromatin organization negative regulation of Wnt signaling pathway negative regulation of transcription, DNA-templated canonical Wnt signaling pathway negative regulation of apoptotic process in utero embryonic development startle response social behavior prepulse inhibition negative regulation of fibroblast apoptotic process Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 57680 67772 Ensembl ENSG00000100888 ENSMUSG00000053754 UniProt Q9HCK8 Q09XV5 RefSeq (mRNA) NM_020920 NM_001170629 NM_001010928 NM_201637 RefSeq (protein) NP_001164100 NP_065971 NP_963999 Location (UCSC) Chr 14: 21.39 – 21.46 Mb Chr 14: 52.44 – 52.5 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Chromodomain-helicase-DNA-binding protein 8 is an enzyme that in humans is encoded by the CHD8 gene. ^{[5] [6]}

Function

The gene CHD8 encodes the protein chromodomain helicase DNA binding protein 8, ^[7] which is a chromatin regulator enzyme that is essential during fetal development. ^[8] CHD8 is an ATP dependent enzyme. ^[9]

The protein contains an Snf2 helicase domain that is responsible for the hydrolysis of ATP to ADP. ^[9] CHD8 encodes for a DNA helicase that function as a transcription repressor by remodeling chromatin structure by altering the position of nucleosomes. ^[8] CHD8 negatively regulates Wnt signaling. ^[10] Wnt signaling is important in the vertebrate early development and morphogenesis. It is believed that CHD8 also recruits the linker histone H1 and causes the repression of β-catenin and p53 target genes. ^[7] The importance of CHD8 can be observed in studies where CHD8-knockout mice died after 5.5 embryonic days because of widespread p53 induced apoptosis. ^[7]

Recently CD8 has been associated to the regulation of long non-coding RNAs (lncRNAs), ^[11] and the regulation of X chromosome inactivation (XCI) initiation, via regulation of Xist long non-coding RNA, the master regulator of XCI, though competitive binding to Xist regulatory regions. ^[12]

Clinical significance

Mutations in this gene have been linked to a subset of autism ^[13] cases in human and mouse models. ^[14]

Mutations in CHD8 could lead to upregulation of β-catenin-regulated genes, in some part of the brain this upregulation can cause brain overgrowth also known as macrocephaly ^[8]

Some studies have determined the role of CHD8 in autism spectrum disorder (ASD). ^[8] CHD8 expression significantly increases during human mid-fetal development. ^[7] The chromatin remodeling activity and its interaction with transcriptional regulators have shown to play an important role in ASD aetiology. ^[15] The developing mammalian brain has a conserved CHD8 target regions that are associated with ASD risk genes. ^[8] The knockdown of CHD8 in human neural stem cells results in dysregulation of ASD risk genes that are targeted by CHD8. ^[16]

References

1. GRCh38: Ensembl release 89: ENSG00000100888 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000053754 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Nagase T, Kikuno R, Nakayama M, Hirosawa M, Ohara O (August 2000). "Prediction of the coding sequences of unidentified human genes. XVIII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro". DNA Research. 7 (4): 273–81. doi: 10.1093/dnares/7.4.271 . PMID   10997877.
6. "Entrez Gene: CHD8 chromodomain helicase DNA binding protein 8".
7. Nishiyama M, Oshikawa K, Tsukada Y, Nakagawa T, Iemura S, Natsume T, et al. (February 2009). "CHD8 suppresses p53-mediated apoptosis through histone H1 recruitment during early embryogenesis". Nature Cell Biology. 11 (2): 172–82. doi:10.1038/ncb1831. PMC   3132516 . PMID   19151705.
8. Ronan JL, Wu W, Crabtree GR (May 2013). "From neural development to cognition: unexpected roles for chromatin". Nature Reviews. Genetics. 14 (5): 347–59. doi:10.1038/nrg3413. PMC   4010428 . PMID   23568486.
9. Thompson BA, Tremblay V, Lin G, Bochar DA (June 2008). "CHD8 is an ATP-dependent chromatin remodeling factor that regulates beta-catenin target genes". Molecular and Cellular Biology. 28 (12): 3894–904. doi:10.1128/MCB.00322-08. PMC   2423111 . PMID   18378692.
10. Nishiyama M, Skoultchi AI, Nakayama KI (January 2012). "Histone H1 recruitment by CHD8 is essential for suppression of the Wnt-β-catenin signaling pathway". Molecular and Cellular Biology. 32 (2): 501–12. doi:10.1128/MCB.06409-11. PMC   3255766 . PMID   22083958.
11. Wilkinson B, Grepo N, Thompson BL, Kim J, Wang K, Evgrafov OV, et al. (May 2015). "The autism-associated gene chromodomain helicase DNA-binding protein 8 (CHD8) regulates noncoding RNAs and autism-related genes". Translational Psychiatry. 5 (5): e568. doi:10.1038/tp.2015.62. ISSN   2158-3188. PMC   4471293 . PMID   25989142.
12. Cerase A, Young AN, Ruiz NB, Buness A, Sant GM, Arnold M, et al. (2021-04-15). "Chd8 regulates X chromosome inactivation in mouse through fine-tuning control of Xist expression". Communications Biology. 4 (1): 485. doi:10.1038/s42003-021-01945-1. ISSN   2399-3642. PMC   8050208 . PMID   33859315.
13. Bernier R, Golzio C, Xiong B, Stessman HA, Coe BP, Penn O, et al. (July 2014). "Disruptive CHD8 mutations define a subtype of autism early in development". Cell. 158 (2): 263–276. doi:10.1016/j.cell.2014.06.017. PMC   4136921 . PMID   24998929.
14. Gompers AL, Su-Feher L, Ellegood J, Copping NA, Riyadh MA, Stradleigh TW, et al. (August 2017). "Germline Chd8 haploinsufficiency alters brain development in mouse". Nature Neuroscience. 20 (8): 1062–1073. doi: 10.1038/nn.4592 . OSTI   1436635. PMC   6008102 . PMID   28671691.
15. Sugathan A, Biagioli M, Golzio C, Erdin S, Blumenthal I, Manavalan P, et al. (October 2014). "CHD8 regulates neurodevelopmental pathways associated with autism spectrum disorder in neural progenitors". Proceedings of the National Academy of Sciences of the United States of America. 111 (42): E4468-77. Bibcode:2014PNAS..111E4468S. doi: 10.1073/pnas.1405266111 . PMC   4210312 . PMID   25294932.
16. Cotney J, Muhle RA, Sanders SJ, Liu L, Willsey AJ, Niu W, et al. (March 2015). "The autism-associated chromatin modifier CHD8 regulates other autism risk genes during human neurodevelopment". Nature Communications. 6 (6): 6404. Bibcode:2015NatCo...6.6404C. doi:10.1038/ncomms7404. PMC   4355952 . PMID   25752243.

External links

• Human CHD8 genome location and CHD8 gene details page in the UCSC Genome Browser .
• Overview of all the structural information available in the PDB for UniProt : Q9HCK8 (Chromodomain-helicase-DNA-binding protein 8) at the PDBe-KB .

Further reading

• Nakajima D, Okazaki N, Yamakawa H, Kikuno R, Ohara O, Nagase T (June 2002). "Construction of expression-ready cDNA clones for KIAA genes: manual curation of 330 KIAA cDNA clones". DNA Research. 9 (3): 99–106. doi: 10.1093/dnares/9.3.99 . PMID   12168954.
• Epplen C, Epplen JT (January 1994). "Expression of (cac)n/(gtg)n simple repetitive sequences in mRNA of human lymphocytes". Human Genetics. 93 (1): 35–41. doi:10.1007/BF00218910. PMID   7505766. S2CID   22998633.
• Sakamoto I, Kishida S, Fukui A, Kishida M, Yamamoto H, Hino S, et al. (October 2000). "A novel beta-catenin-binding protein inhibits beta-catenin-dependent Tcf activation and axis formation". The Journal of Biological Chemistry. 275 (42): 32871–8. doi: 10.1074/jbc.M004089200 . PMID   10921920.
• Kobayashi M, Hanai R (September 2001). "M phase-specific association of human topoisomerase IIIbeta with chromosomes". Biochemical and Biophysical Research Communications. 287 (1): 282–7. doi:10.1006/bbrc.2001.5580. PMID   11549288.
• Kobayashi M, Kishida S, Fukui A, Michiue T, Miyamoto Y, Okamoto T, et al. (February 2002). "Nuclear localization of Duplin, a beta-catenin-binding protein, is essential for its inhibitory activity on the Wnt signaling pathway". The Journal of Biological Chemistry. 277 (8): 5816–22. doi: 10.1074/jbc.M108433200 . PMID   11744694.
• Nishiyama M, Nakayama K, Tsunematsu R, Tsukiyama T, Kikuchi A, Nakayama KI (October 2004). "Early embryonic death in mice lacking the beta-catenin-binding protein Duplin". Molecular and Cellular Biology. 24 (19): 8386–94. doi:10.1128/MCB.24.19.8386-8394.2004. PMC   516734 . PMID   15367660.
• Lin KT, Lu RM, Tarn WY (October 2004). "The WW domain-containing proteins interact with the early spliceosome and participate in pre-mRNA splicing in vivo". Molecular and Cellular Biology. 24 (20): 9176–85. doi:10.1128/MCB.24.20.9176-9185.2004. PMC   517884 . PMID   15456888.
• Ishihara K, Oshimura M, Nakao M (September 2006). "CTCF-dependent chromatin insulator is linked to epigenetic remodeling". Molecular Cell. 23 (5): 733–42. doi: 10.1016/j.molcel.2006.08.008 . PMID   16949368.
• Beausoleil SA, Villén J, Gerber SA, Rush J, Gygi SP (October 2006). "A probability-based approach for high-throughput protein phosphorylation analysis and site localization". Nature Biotechnology. 24 (10): 1285–92. doi:10.1038/nbt1240. PMID   16964243. S2CID   14294292.
• Olsen JV, Blagoev B, Gnad F, Macek B, Kumar C, Mortensen P, et al. (November 2006). "Global, in vivo, and site-specific phosphorylation dynamics in signaling networks". Cell. 127 (3): 635–48. doi: 10.1016/j.cell.2006.09.026 . PMID   17081983.
• Yuan CC, Zhao X, Florens L, Swanson SK, Washburn MP, Hernandez N (December 2007). "CHD8 associates with human Staf and contributes to efficient U6 RNA polymerase III transcription". Molecular and Cellular Biology. 27 (24): 8729–38. doi:10.1128/MCB.00846-07. PMC   2169411 . PMID   17938208.
• Thompson BA, Tremblay V, Lin G, Bochar DA (June 2008). "CHD8 is an ATP-dependent chromatin remodeling factor that regulates beta-catenin target genes". Molecular and Cellular Biology. 28 (12): 3894–904. doi:10.1128/MCB.00322-08. PMC   2423111 . PMID   18378692.
• Caldon CE, Sergio CM, Schütte J, Boersma MN, Sutherland RL, Carroll JS, et al. (September 2009). "Estrogen regulation of cyclin E2 requires cyclin D1 but not c-Myc". Molecular and Cellular Biology. 29 (17): 4623–39. doi:10.1128/MCB.00269-09. PMC   2725719 . PMID   19564413.
• Nishiyama M, Oshikawa K, Tsukada Y, Nakagawa T, Iemura S, Natsume T, et al. (February 2009). "CHD8 suppresses p53-mediated apoptosis through histone H1 recruitment during early embryogenesis". Nature Cell Biology. 11 (2): 172–82. doi:10.1038/ncb1831. PMC   3132516 . PMID   19151705.
• Rodríguez-Paredes M, Ceballos-Chávez M, Esteller M, García-Domínguez M, Reyes JC (May 2009). "The chromatin remodeling factor CHD8 interacts with elongating RNA polymerase II and controls expression of the cyclin E2 gene". Nucleic Acids Research. 37 (8): 2449–60. doi:10.1093/nar/gkp101. PMC   2677868 . PMID   19255092.
• Yates JA, Menon T, Thompson BA, Bochar DA (February 2010). "Regulation of HOXA2 gene expression by the ATP-dependent chromatin remodeling enzyme CHD8" (PDF). FEBS Letters. 584 (4): 689–93. doi:10.1016/j.febslet.2010.01.022. hdl: 2027.42/116349 . PMID   20085832. S2CID   9956275.