CHD8 explained

Chromodomain-helicase-DNA-binding protein 8 is an enzyme that in humans is encoded by the CHD8 gene.^{[1] [2]}

Function

The gene CHD8 encodes the protein chromodomain helicase DNA binding protein 8,^[3] which is a chromatin regulator enzyme that is essential during fetal development.^[4] CHD8 is an ATP dependent enzyme.^[5]

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

Recently CD8 has been associated to the regulation of long non-coding RNAs (lncRNAs),^[7] 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.^[8]

Clinical significance

Mutations in this gene have been linked to a subset of autism^[9] cases in human and mouse models.^[10]

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

Some studies have determined the role of CHD8 in autism spectrum disorder (ASD). CHD8 expression significantly increases during human mid-fetal development. The chromatin remodeling activity and its interaction with transcriptional regulators have shown to play an important role in ASD aetiology.^[11] The developing mammalian brain has a conserved CHD8 target regions that are associated with ASD risk genes. The knockdown of CHD8 in human neural stem cells results in dysregulation of ASD risk genes that are targeted by CHD8.^[12]

Further reading

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

Notes and References

1. Nagase T, Kikuno R, Nakayama M, Hirosawa M, Ohara O . 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 . August 2000 . 10997877 . 10.1093/dnares/7.4.271 . free .
2. Web site: Entrez Gene: CHD8 chromodomain helicase DNA binding protein 8.
3. Nishiyama M, Oshikawa K, Tsukada Y, Nakagawa T, Iemura S, Natsume T, Fan Y, Kikuchi A, Skoultchi AI, Nakayama KI . CHD8 suppresses p53-mediated apoptosis through histone H1 recruitment during early embryogenesis . Nature Cell Biology . 11 . 2 . 172–82 . February 2009 . 19151705 . 3132516 . 10.1038/ncb1831 .
4. Ronan JL, Wu W, Crabtree GR . From neural development to cognition: unexpected roles for chromatin . Nature Reviews. Genetics . 14 . 5 . 347–59 . May 2013 . 23568486 . 4010428 . 10.1038/nrg3413 .
5. Thompson BA, Tremblay V, Lin G, Bochar DA . CHD8 is an ATP-dependent chromatin remodeling factor that regulates beta-catenin target genes . Molecular and Cellular Biology . 28 . 12 . 3894–904 . June 2008 . 18378692 . 2423111 . 10.1128/MCB.00322-08 .
6. Nishiyama M, Skoultchi AI, Nakayama KI . Histone H1 recruitment by CHD8 is essential for suppression of the Wnt-β-catenin signaling pathway . Molecular and Cellular Biology . 32 . 2 . 501–12 . January 2012 . 22083958 . 3255766 . 10.1128/MCB.06409-11 .
7. Wilkinson . B . Grepo . N . Thompson . B L . Kim . J . Wang . K . Evgrafov . O V . Lu . W . Knowles . J A . Campbell . D B . 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 . 10.1038/tp.2015.62 . 25989142 . 4471293 . 2158-3188.
8. Cerase . Andrea . Young . Alexander N. . Ruiz . Nerea Blanes . Buness . Andreas . Sant . Gabrielle M. . Arnold . Mirjam . Di Giacomo . Monica . Ascolani . Michela . Kumar . Manish . Hierholzer . Andreas . Trigiante . Giuseppe . 2021-04-15 . Chd8 regulates X chromosome inactivation in mouse through fine-tuning control of Xist expression . Communications Biology . 4 . 1 . 485 . 10.1038/s42003-021-01945-1 . 33859315 . 8050208 . 2399-3642.
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 . Disruptive CHD8 mutations define a subtype of autism early in development . Cell . 158 . 2 . 263–276 . July 2014 . 24998929 . 4136921 . 10.1016/j.cell.2014.06.017 .
10. Gompers AL, Su-Feher L, Ellegood J, Copping NA, Riyadh MA, Stradleigh TW, Pride MC, Schaffler MD, Wade AA, Catta-Preta R, Zdilar I, Louis S, Kaushik G, Mannion BJ, Plajzer-Frick I, Afzal V, Visel A, Pennacchio LA, Dickel DE, Lerch JP, Crawley JN, Zarbalis KS, Silverman JL, Nord AS . Germline Chd8 haploinsufficiency alters brain development in mouse . Nature Neuroscience . 20 . 8 . 1062–1073 . August 2017 . 28671691 . 10.1038/nn.4592 . 6008102 . 1436635 . free .
11. 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 . 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 . October 2014 . 25294932 . 4210312 . 10.1073/pnas.1405266111 . free . 2014PNAS..111E4468S .
12. 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 . The autism-associated chromatin modifier CHD8 regulates other autism risk genes during human neurodevelopment . Nature Communications . 6 . 6 . 6404 . March 2015 . 25752243 . 4355952 . 10.1038/ncomms7404 . 2015NatCo...6.6404C .