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
External IDs	MGI: 1915022 HomoloGene: 72405 GeneCards: CHD8
Gene ontology Molecular function • DNA binding • nucleotide binding • DNA-dependent ATPase activity • beta-catenin binding • helicase activity • histone binding • p53 binding • chromatin binding • methylated histone binding • hydrolase activity, acting on acid anhydrides • DNA helicase activity • protein binding • armadillo repeat domain binding • hydrolase activity • ATP binding Cellular component • nucleoplasm • protein complex • MLL1 complex • nucleus Biological process • regulation of transcription, DNA-templated • negative regulation of Wnt signaling pathway • negative regulation of apoptotic process • in utero embryonic development • negative regulation of transcription from RNA polymerase II promoter • Wnt signaling pathway • transcription, DNA-templated • ATP-dependent chromatin remodeling • positive regulation of transcription, DNA-templated • brain development • canonical Wnt signaling pathway • negative regulation of fibroblast apoptotic process • digestive tract development • negative regulation of transcription, DNA-templated • positive regulation of transcription from RNA polymerase III promoter • negative regulation of canonical Wnt signaling pathway • positive regulation of transcription from RNA polymerase II promoter • DNA duplex unwinding • covalent chromatin modification Sources:Amigo / QuickGO
RNA expression pattern
More reference expression data
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_001164100.1 NP_065971.2	NP_963999.2
Location (UCSC)	Chr 14: 21.39 – 21.46 Mb	Chr 14: 52.2 – 52.26 Mb
PubMed search	[1]	[2]
Wikidata

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Chromodomain-helicase-DNA-binding protein 8 is an enzyme that in humans is encoded by the CHD8 gene.^[3][4]

Function

The gene CHD8 encodes the protein chromodomain helicase DNA binding protein 8,^[5] which is a chromatin regulator enzyme that is essential during fetal development.^[6] CHD8 is an ATP dependent enzyme.^[7]

The protein contains an Snf2 helicase domain that is responsible for the hydrolysis of ATP to ADP.^[7] CHD8 encodes for a DNA helicase that function as a transcription repressor by remodeling chromatin structure by altering the position of nucleosomes.^[6] CHD8 negatively regulates Wnt signaling.^[8] 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.^[5] 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.^[5]

Clinical significance

Mutations in this gene have been linked to a subset of autism^[9] cases.

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, which occurs in 15-35% of autistic children.^[6]

Some studies have determined the role of CHD8 in autism spectrum disorder (ASD).^[6] CDH8 expression significantly increases during human mid-fetal development.^[5] The chromatin remodeling activity and its interaction with transcriptional regulators have shown to play an important role in ASD aetiology.^[10] The developing mammalian brain has a conserved CHD8 target regions that are associated with ASD risk genes.^[6] The knockdown of CHD8 in human neural stem cells results in dysregulation of ASD risk genes that are targeted by CHD8.^[11]

References

1. "Human PubMed Reference:".
2. "Mouse PubMed Reference:".
3. Nagase T, Kikuno R, Nakayama M, Hirosawa M, Ohara O (Aug 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.
4. "Entrez Gene: CHD8 chromodomain helicase DNA binding protein 8".
5. Nishiyama M, Oshikawa K, Tsukada Y, Nakagawa T, Iemura S, Natsume T, Fan Y, Kikuchi A, Skoultchi AI, Nakayama KI (Feb 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.
6. 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. PMID 23568486.
7. Thompson BA, Tremblay V, Lin G, Bochar DA (Jun 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.
8. Nishiyama M, Skoultchi AI, Nakayama KI (Jan 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. PMID 22083958.
9. Bernier R, Golzio C, Xiong B, Stessman HA, Coe BP, Penn O, Witherspoon K, Gerdts J, Baker C, Vulto-van Silfhout AT, Schuurs-Hoeijmakers JH, Fichera M, Bosco P, Buono S, Alberti A, Failla P, Peeters H, Steyaert J, Vissers LE, Francescatto L, Mefford HC, Rosenfeld JA, Bakken T, O'Roak BJ, Pawlus M, Moon R, Shendure J, Amaral DG, Lein E, Rankin J, Romano C, de Vries BB, Katsanis N, Eichler EE (Jul 2014). "Disruptive CHD8 mutations define a subtype of autism early in development". Cell. 158 (2): 263–76. doi:10.1016/j.cell.2014.06.017. PMC 4136921. PMID 24998929.
10. Sugathan A, Biagioli M, Golzio C, Erdin S, Blumenthal I, Manavalan P, Ragavendran A, Brand H, Lucente D, Miles J, Sheridan SD, Stortchevoi A, Kellis M, Haggarty SJ, Katsanis N, Gusella JF, Talkowski ME (Oct 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. doi:10.1073/pnas.1405266111. PMID 25294932.
11. Cotney J, Muhle RA, Sanders SJ, Liu L, Willsey AJ, Niu W, Liu W, Klei L, Lei J, Yin J, Reilly SK, Tebbenkamp AT, Bichsel C, Pletikos M, Sestan N, Roeder K, State MW, Devlin B, Noonan JP (2015). "The autism-associated chromatin modifier CHD8 regulates other autism risk genes during human neurodevelopment". Nature Communications. 6 (6): 6404. doi:10.1038/ncomms7404. PMID 25752243.

Further reading

• Nakajima D, Okazaki N, Yamakawa H, Kikuno R, Ohara O, Nagase T (Jun 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 (Jan 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.
• Sakamoto I, Kishida S, Fukui A, Kishida M, Yamamoto H, Hino S, Michiue T, Takada S, Asashima M, Kikuchi A (Oct 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 (Sep 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, Yoneda Y, Asashima M, Kikuchi A (Feb 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 (Oct 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 (Oct 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 (Sep 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 (Oct 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.
• Olsen JV, Blagoev B, Gnad F, Macek B, Kumar C, Mortensen P, Mann M (Nov 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 (Dec 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 (Jun 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, Musgrove EA (Sep 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, Fan Y, Kikuchi A, Skoultchi AI, Nakayama KI (Feb 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 (Feb 2010). "Regulation of HOXA2 gene expression by the ATP-dependent chromatin remodeling enzyme CHD8". FEBS Letters. 584 (4): 689–93. doi:10.1016/j.febslet.2010.01.022. PMID 20085832.