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.[5] CHD8 encodes for a DNA helicase that function as a transcription repressor by remodeling chromatin structure by altering the position of nucleosomes.[4] 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.[3] 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.[3]
Clinical significance
Mutations in this gene have been linked to a subset of autism[7] 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.[4]
Some studies have determined the role of CHD8 in autism spectrum disorder (ASD).[4] CHD8 expression significantly increases during human mid-fetal development.[3] The chromatin remodeling activity and its interaction with transcriptional regulators have shown to play an important role in ASD aetiology.[8] The developing mammalian brain has a conserved CHD8 target regions that are associated with ASD risk genes.[4] The knockdown of CHD8 in human neural stem cells results in dysregulation of ASD risk genes that are targeted by CHD8.[9]
References
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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. PMID12168954.
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. PMID7505766.
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. PMID10921920.
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. PMID11549288.
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. PMID11744694.
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. PMID16949368.
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. PMID16964243.
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. PMID17081983.
