# CHD2

## Overview
CHD2, or chromodomain helicase DNA binding protein 2, is a gene that encodes a protein involved in chromatin remodeling, a critical process for regulating gene expression. The CHD2 protein is a member of the chromodomain helicase DNA-binding (CHD) family and plays a pivotal role in modifying chromatin structure to facilitate access to the transcriptional machinery, thereby influencing gene expression across various biological processes and developmental stages. This protein is particularly significant in brain development and has been linked to several neurodevelopmental disorders when mutated. CHD2 functions through its interaction with other proteins and DNA, utilizing its chromodomains for binding to methylated histones and its helicase domains to alter nucleosome structure (Harada2012Chd2; Lewis2022Regulation).

## Structure
The CHD2 protein, encoded by the CHD2 gene, is characterized by a complex molecular structure integral to its function in chromatin remodeling. The protein features several functional domains, including double chromodomains at the N-terminal region and a central SNF2 helicase-like ATPase domain. These chromodomains are essential for binding to methylated lysines on histone H3 tails and other nucleic acids, serving as nucleosome recognition modules and allosteric regulators of the ATPase activity (Alendar2021Sentinels). The ATPase domain, a hallmark of the SF2 helicase family, facilitates ATP hydrolysis, driving changes in histone-DNA contacts within the nucleosome to alter chromatin structure (Alendar2021Sentinels; Cardoso2021Genetic).

Additionally, CHD2 contains Helicase ATP-binding and Helicase C-terminal domains, which include highly conserved motifs crucial for helicase activity. Mutations in these motifs can lead to dysfunction and are linked to neurodevelopmental disorders (Cardoso2021Genetic). The protein also undergoes various post-translational modifications and exists in multiple isoforms due to alternative promoter usage or splicing, adding layers to its functional diversity (Alendar2021Sentinels).

While specific details on the primary, secondary, tertiary, or quaternary structures of CHD2 are not provided in the available literature, the described domains and motifs play critical roles in the protein's function and interaction with chromatin substrates.

## Function
CHD2 (chromodomain helicase DNA binding protein 2) is a member of the chromodomain helicase DNA-binding (CHD) family, involved in chromatin remodeling. This protein plays a crucial role in gene regulation by modifying the accessibility of chromatin to the transcriptional machinery, thus influencing gene expression essential for various cellular processes including cell viability, growth, and differentiation (Marfella2006Mutation). CHD2 is particularly significant in brain development, especially in the differentiation and function of cortical interneurons. It regulates gene expression by binding to genomic regions coenriched with histone H3 lysine 27 acetylation (H3K27ac), a marker associated with active gene transcription (Lewis2022Regulation).

In the context of neurogenesis, CHD2 is crucial for maintaining the self-renewal capacity of radial glia, progenitor cells in the brain, and for regulating the balance between the proliferation and differentiation of these cells (Shen2015CHD2). Additionally, CHD2 interacts with the REST gene, a known repressor of neuronal genes, suggesting a role in influencing gene expression related to neurogenesis (Shen2015CHD2).

Mutations in CHD2 have been linked to neurodevelopmental disorders, underscoring its importance in maintaining normal brain function and development (Lewis2022Regulation).

## Clinical Significance
Mutations in the CHD2 gene are primarily linked to a spectrum of neurodevelopmental disorders and epileptic conditions. CHD2-related diseases manifest with a variety of seizure types, including myoclonic, absence, generalized tonic-clonic, and focal seizures, often accompanied by developmental delays and intellectual disabilities. The onset of these conditions typically occurs in early childhood, with some cases presenting in adulthood (De2021Expanding). 

CHD2 mutations are also associated with photosensitivity, which can manifest both clinically and electrographically. This gene's role in epilepsy is further highlighted by its association with fever-sensitive myoclonic epileptic encephalopathy, sharing features with Dravet syndrome, a severe form of epilepsy (Suls2013De). 

Moreover, CHD2 gene disruptions are implicated in various other neurological disorders. Research has shown that haploinsufficiency of CHD2 leads to significant changes in genes critical for nervous system development, neuron differentiation, and synaptic plasticity, linking it to conditions like autism spectrum disorders and intellectual disability (Kim2018Chd2).

In summary, CHD2 mutations have profound impacts on neurological development and function, leading to a range of severe clinical outcomes, including drug-resistant epilepsy and significant developmental delay (Chen2019CHD2‐related).

## Interactions
CHD2 interacts with various proteins and nucleic acids, playing a significant role in chromatin remodeling and gene expression regulation. One notable interaction is with the histone variant H3.3, particularly in the context of myogenic gene expression and cell differentiation. CHD2 specifically associates with H3.3, differentiating it from other histone H3 variants like H3.1. This interaction is crucial for the incorporation of H3.3 into chromatin at myogenic gene loci, marking these genes for expression during differentiation (Harada2012Chd2).

Additionally, CHD2 interacts with the myogenic transcription factor MyoD. This interaction is essential for the determination of myogenic cell fate, as CHD2 and MyoD co-localize and are co-recruited to myogenic gene promoters, influencing the transcriptional activation of these genes during muscle cell differentiation (Harada2012Chd2).

In the context of chronic lymphocytic leukemia, CHD2 variants, including mutants, have been shown to interact with active chromatin marks such as H3K4me3 and H4Ac. However, the CHD2 L1270F mutant exhibits a functional defect in colocalizing with actively transcribed chromatin, attributed to an impaired DNA-binding domain (Rodríguez2015Mutations).

These interactions underline CHD2's role in chromatin architecture modulation and its impact on gene expression across different cellular contexts.


## References


[1. (De2021Expanding) Beatrice De Maria, Simona Balestrini, Davide Mei, Federico Melani, Simona Pellacani, Tiziana Pisano, Anna Rosati, Giusi M. Scaturro, Lucio Giordano, Gaetano Cantalupo, Elena Fontana, Cristina Zammarchi, Edith Said, Vincenzo Leuzzi, Mario Mastrangelo, Serena Galosi, Elena Parrini, and Renzo Guerrini. Expanding the genetic and phenotypic spectrum of <scp>chd2</scp>‐related disease: from early neurodevelopmental disorders to adult‐onset epilepsy. American Journal of Medical Genetics Part A, 188(2):522–533, October 2021. URL: http://dx.doi.org/10.1002/ajmg.a.62548, doi:10.1002/ajmg.a.62548. (13 citations) 10.1002/ajmg.a.62548](https://doi.org/10.1002/ajmg.a.62548)

[2. (Kim2018Chd2) Young J. Kim, Sattar Khoshkhoo, Jan C. Frankowski, Bingyao Zhu, Saad Abbasi, Sunyoung Lee, Ye Emily Wu, and Robert F. Hunt. Chd2 is necessary for neural circuit development and long-term memory. Neuron, 100(5):1180-1193.e6, December 2018. URL: http://dx.doi.org/10.1016/j.neuron.2018.09.049, doi:10.1016/j.neuron.2018.09.049. (64 citations) 10.1016/j.neuron.2018.09.049](https://doi.org/10.1016/j.neuron.2018.09.049)

[3. (Alendar2021Sentinels) Andrej Alendar and Anton Berns. Sentinels of chromatin: chromodomain helicase dna-binding proteins in development and disease. Genes &amp; Development, 35(21–22):1403–1430, November 2021. URL: http://dx.doi.org/10.1101/gad.348897.121, doi:10.1101/gad.348897.121. (21 citations) 10.1101/gad.348897.121](https://doi.org/10.1101/gad.348897.121)

[4. (Lewis2022Regulation) E. M. A. Lewis, G. Chapman, K. Kaushik, J. Determan, I. Antony, K. Meganathan, M. Narasimhan, P. Gontarz, B. Zhang, and K. L. Kroll. Regulation of human cortical interneuron development by the chromatin remodeling protein chd2. Scientific Reports, September 2022. URL: http://dx.doi.org/10.1038/s41598-022-19654-y, doi:10.1038/s41598-022-19654-y. (3 citations) 10.1038/s41598-022-19654-y](https://doi.org/10.1038/s41598-022-19654-y)

[5. (Marfella2006Mutation) Concetta G.A. Marfella, Yasuyuki Ohkawa, Andrew H. Coles, David S. Garlick, Stephen N. Jones, and Anthony N. Imbalzano. Mutation of the snf2 family member chd2 affects mouse development and survival. Journal of Cellular Physiology, 209(1):162–171, June 2006. URL: http://dx.doi.org/10.1002/jcp.20718, doi:10.1002/jcp.20718. (113 citations) 10.1002/jcp.20718](https://doi.org/10.1002/jcp.20718)

[6. (Cardoso2021Genetic) Ana R. Cardoso, Mónica Lopes-Marques, Manuela Oliveira, António Amorim, Maria J. Prata, and Luísa Azevedo. Genetic variability of the functional domains of chromodomains helicase dna-binding (chd) proteins. Genes, 12(11):1827, November 2021. URL: http://dx.doi.org/10.3390/genes12111827, doi:10.3390/genes12111827. (8 citations) 10.3390/genes12111827](https://doi.org/10.3390/genes12111827)

[7. (Harada2012Chd2) Akihito Harada, Seiji Okada, Daijiro Konno, Jun Odawara, Tomohiko Yoshimi, Saori Yoshimura, Hiromi Kumamaru, Hirokazu Saiwai, Toshiaki Tsubota, Hitoshi Kurumizaka, Koichi Akashi, Taro Tachibana, Anthony N Imbalzano, and Yasuyuki Ohkawa. Chd2 interacts with h3.3 to determine myogenic cell fate: chd2 incorporates h3.3 to mark myogenic genes. The EMBO Journal, 31(13):2994–3007, May 2012. URL: http://dx.doi.org/10.1038/emboj.2012.136, doi:10.1038/emboj.2012.136. (136 citations) 10.1038/emboj.2012.136](https://doi.org/10.1038/emboj.2012.136)

[8. (Chen2019CHD2‐related) Jiaoyang Chen, Jing Zhang, Aijie Liu, Liping Zhang, Hua Li, Qi Zeng, Zhixian Yang, Xiaoling Yang, Xiru Wu, and Yuehua Zhang. Chd2‐related epilepsy: novel mutations and new phenotypes. Developmental Medicine &amp; Child Neurology, 62(5):647–653, November 2019. URL: http://dx.doi.org/10.1111/dmcn.14367, doi:10.1111/dmcn.14367. (24 citations) 10.1111/dmcn.14367](https://doi.org/10.1111/dmcn.14367)

[9. (Rodríguez2015Mutations) David Rodríguez, Gabriel Bretones, Víctor Quesada, Neus Villamor, Javier R. Arango, Armando López-Guillermo, Andrew J. Ramsay, Tycho Baumann, Pedro M. Quirós, Alba Navarro, Cristina Royo, José I. Martín-Subero, Elías Campo, and Carlos López-Otín. Mutations in chd2 cause defective association with active chromatin in chronic lymphocytic leukemia. Blood, 126(2):195–202, July 2015. URL: http://dx.doi.org/10.1182/blood-2014-10-604959, doi:10.1182/blood-2014-10-604959. (50 citations) 10.1182/blood-2014-10-604959](https://doi.org/10.1182/blood-2014-10-604959)

[10. (Shen2015CHD2) Tianjin Shen, Fen Ji, Zengqiang Yuan, and Jianwei Jiao. Chd2 is required for embryonic neurogenesis in the developing cerebral cortex. Stem Cells, 33(6):1794–1806, May 2015. URL: http://dx.doi.org/10.1002/stem.2001, doi:10.1002/stem.2001. (59 citations) 10.1002/stem.2001](https://doi.org/10.1002/stem.2001)

[11. (Suls2013De) Arvid Suls, Johanna A. Jaehn, Angela Kecskés, Yvonne Weber, Sarah Weckhuysen, Dana C. Craiu, Aleksandra Siekierska, Tania Djémié, Tatiana Afrikanova, Padhraig Gormley, Sarah von Spiczak, Gerhard Kluger, Catrinel M. Iliescu, Tiina Talvik, Inga Talvik, Cihan Meral, Hande S. Caglayan, Beatriz G. Giraldez, José Serratosa, Johannes R. Lemke, Dorota Hoffman-Zacharska, Elzbieta Szczepanik, Nina Barisic, Vladimir Komarek, Helle Hjalgrim, Rikke S. Møller, Tarja Linnankivi, Petia Dimova, Pasquale Striano, Federico Zara, Carla Marini, Renzo Guerrini, Christel Depienne, Stéphanie Baulac, Gregor Kuhlenbäumer, Alexander D. Crawford, Anna-Elina Lehesjoki, Peter A.M. de Witte, Aarno Palotie, Holger Lerche, Camila V. Esguerra, Peter De Jonghe, Ingo Helbig, Rik Hendrickx, Philip Holmgren, Ulrich Stephani, Hiltrud Muhle, Manuela Pendiziwiat, Silke Appenzeller, Kaja Selmer, Eva Brilstra, Bobby Koeleman, Felix Rosenow, Eric Leguern, Katalin Sterbova, Budisteanu Magdalena, Gherghiceanu Rodica, Oana Tarta Arsene, Barca Diana, Rosa Guerrero-Lopez, Laura Ortega, Albena P. Todorova, Andrey V. Kirov, Angela Robbiano, Mutluay Arslan, Uluç Yiş, and Vanja Ivanović. De novo loss-of-function mutations in chd2 cause a fever-sensitive myoclonic epileptic encephalopathy sharing features with dravet syndrome. The American Journal of Human Genetics, 93(5):967–975, November 2013. URL: http://dx.doi.org/10.1016/j.ajhg.2013.09.017, doi:10.1016/j.ajhg.2013.09.017. (176 citations) 10.1016/j.ajhg.2013.09.017](https://doi.org/10.1016/j.ajhg.2013.09.017)