# MEF2C

## Overview
The MEF2C gene encodes the myocyte enhancer factor 2C, a transcription factor belonging to the MADS-box family, which is pivotal in regulating gene expression across various cell types, including muscle, neural, endothelial, and immune cells. The MEF2C protein is characterized by its ability to bind A/T-rich DNA sequences and form homo- and heterodimers, facilitating its role in muscle differentiation, neuronal survival, and vascular integrity (Molkentin1996Mutational; Kobarg2005MEF2C). It is involved in critical developmental processes, such as myogenesis and cardiogenesis, and modulates cellular responses through interactions with multiple signaling pathways and regulatory proteins (Xu2015Transcription; Dong2017Myocyte). Dysregulation of MEF2C is linked to various clinical conditions, including neurodevelopmental disorders and congenital heart defects, underscoring its importance in maintaining cellular and tissue homeostasis (Lu2018A; Rocha2016MEF2C).

## Structure
The MEF2C protein is a member of the MADS-box family of transcription factors, characterized by a conserved MADS domain responsible for DNA binding and dimerization (Molkentin1996Mutational). The human MEF2C protein consists of 473 amino acids and includes six domains: MADS, MEF2, HJURP-C, TAD1, TAD2, and NLS (Dong2017Myocyte). The MADS domain, located at the N-terminus, is highly conserved and mediates DNA binding, dimerization, and co-factor interactions (Dong2017Myocyte). The MEF2 domain, adjacent to the MADS domain, influences DNA binding and indirectly supports dimerization by maintaining structural integrity (Molkentin1996Mutational).

The C-terminal region of MEF2C contains transcription activation domains, specifically between residues 143 to 174 and 247 to 327, which are rich in serine, threonine, and proline residues (Molkentin1996Mutational). These regions are crucial for transcriptional activation (Molkentin1996Mutational). Phosphorylation of serine 59, located between the MADS and MEF2 domains, enhances DNA binding and transcriptional activity, indicating the importance of post-translational modifications in regulating MEF2C's function (Molkentin1996Phosphorylation).

The MEF2C protein can form homo- and heterodimers, binding to A/T-rich DNA sequences, and is involved in various biological functions, including muscle and neural development (Kobarg2005MEF2C). The interaction with regulatory proteins, such as Ki-1/57, can inhibit its DNA-binding activity, suggesting a complex regulatory mechanism (Kobarg2005MEF2C).

## Function
MEF2C (myocyte enhancer factor 2C) is a transcription factor that plays a critical role in the development and function of various cell types, including muscle, neural, endothelial, and immune cells. In muscle cells, MEF2C is essential for maintaining sarcomere integrity and regulating the expression of genes involved in muscle contraction and cytoskeletal organization, such as myomesin and M protein (Potthoff2007Regulation). It interacts with myogenic regulatory factors to facilitate myogenesis, the process of muscle cell formation, and influences muscle-specific gene expression through interactions with proteins like MyoD and desmin (Dong2017Myocyte).

In the nervous system, MEF2C is involved in neuronal differentiation and survival, playing a role in protecting neurons from apoptosis and contributing to learning and memory (Dong2017Myocyte). It also regulates endothelial cell function by suppressing inflammation and maintaining vascular integrity, acting as an inhibitor of pro-inflammatory pathways and leukocyte adhesion (Xu2015Transcription).

MEF2C's activity is modulated by interactions with various proteins and signaling pathways, including the MAP kinase pathway, which enhances its transcriptional activity through phosphorylation (Black1998TRANSCRIPTIONAL). These interactions highlight MEF2C's multifaceted role in regulating gene expression and maintaining cellular and tissue homeostasis.

## Clinical Significance
Mutations and alterations in the MEF2C gene are associated with a range of neurodevelopmental disorders. MEF2C haploinsufficiency syndrome, caused by mutations or deletions in the MEF2C gene, is characterized by severe intellectual disability, epilepsy, stereotypic movements, and minor dysmorphic features (Le2009MEF2C; Rocha2016MEF2C). Patients often exhibit developmental delays, absent speech, and hypotonia, with some showing brain anomalies on MRI (Wang2018Novel). 

MEF2C mutations are also linked to conditions resembling Rett syndrome, a disorder marked by developmental regression and stereotypic hand movements, although most patients with MEF2C mutations present with a variant form featuring congenital hypotonia and early-onset seizures (Zweier2010Mutations). The gene's dysfunction is implicated in autism spectrum disorder (ASD)-like syndromes, as MEF2C knockout mice display increased excitatory synapses and ASD-like social behavior defects (Zhang2022Progress).

In addition to neurodevelopmental disorders, MEF2C mutations are associated with congenital heart defects, such as double outlet right ventricle, due to its role in cardiogenesis (Lu2018A). The gene's altered expression is also implicated in the development and progression of nervous system tumors (Zhang2022Progress).

## Interactions
MEF2C interacts with a variety of proteins, playing a crucial role in muscle differentiation, cardiac development, and other biological processes. It forms complexes with myogenic regulatory factors (MRFs) such as MyoD, Myogenin, Myf5, and MRF4, which are essential for myoblast specification and differentiation (Dong2017Myocyte). MEF2C also interacts with the transcriptional coactivator p300, which enhances its transcriptional activation capabilities by binding to the MADS domain of MEF2C (Sartorelli1997Molecular).

In cardiac development, MEF2C interacts with TBX5, a transcription factor crucial for early heart development. This interaction is necessary for the activation of cardiac-specific genes like the α-cardiac myosin heavy chain (MYH6) gene (Ghosh2009Physical). MEF2C also interacts with GATA4, forming a complex that influences cardiac hypertrophy and signaling pathways (Dong2017Myocyte).

MEF2C's interaction with histone deacetylases (HDACs) is significant for transcriptional repression, while its interaction with the regulatory protein Ki-1/57 inhibits its DNA-binding activity, suggesting a role in cardiac hypertrophy regulation (Kobarg2005MEF2C). These interactions highlight MEF2C's multifaceted role in regulating gene expression across different tissues and developmental stages.


## References


[1. (Zhang2022Progress) Zhikun Zhang and Yongxiang Zhao. Progress on the roles of mef2c in neuropsychiatric diseases. Molecular Brain, January 2022. URL: http://dx.doi.org/10.1186/s13041-021-00892-6, doi:10.1186/s13041-021-00892-6. This article has 26 citations and is from a peer-reviewed journal.](https://doi.org/10.1186/s13041-021-00892-6)

[2. (Kobarg2005MEF2C) Claudia Bandeira Kobarg, Jörg Kobarg, Daniella P. Crosara-Alberto, Thaís Holtz Theizen, and Kleber Gomes Franchini. Mef2c dna‐binding activity is inhibited through its interaction with the regulatory protein ki‐1/57. FEBS Letters, 579(12):2615–2622, April 2005. URL: http://dx.doi.org/10.1016/j.febslet.2005.03.078, doi:10.1016/j.febslet.2005.03.078. This article has 14 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.febslet.2005.03.078)

[3. (Potthoff2007Regulation) Matthew J. Potthoff, Michael A. Arnold, John McAnally, James A. Richardson, Rhonda Bassel-Duby, and Eric N. Olson. Regulation of skeletal muscle sarcomere integrity and postnatal muscle function by mef2c. Molecular and Cellular Biology, 27(23):8143–8151, December 2007. URL: http://dx.doi.org/10.1128/MCB.01187-07, doi:10.1128/mcb.01187-07. This article has 258 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1128/MCB.01187-07)

[4. (Molkentin1996Mutational) Jeffery D. Molkentin, Brian L. Black, James F. Martin, and Eric N. Olson. Mutational analysis of the dna binding, dimerization, and transcriptional activation domains of mef2c. Molecular and Cellular Biology, 16(6):2627–2636, June 1996. URL: http://dx.doi.org/10.1128/mcb.16.6.2627, doi:10.1128/mcb.16.6.2627. This article has 166 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1128/mcb.16.6.2627)

[5. (Le2009MEF2C) N. Le Meur, M. Holder-Espinasse, S. Jaillard, A. Goldenberg, S. Joriot, P. Amati-Bonneau, A. Guichet, M. Barth, A. Charollais, H. Journel, S. Auvin, C. Boucher, J.-P. Kerckaert, V. David, S. Manouvrier-Hanu, P. Saugier-Veber, T. Frebourg, C. Dubourg, J. Andrieux, and D. Bonneau. Mef2c haploinsufficiency caused by either microdeletion of the 5q14.3 region or mutation is responsible for severe mental retardation with stereotypic movements, epilepsy and/or cerebral malformations. Journal of Medical Genetics, 47(1):22–29, July 2009. URL: http://dx.doi.org/10.1136/jmg.2009.069732, doi:10.1136/jmg.2009.069732. This article has 178 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1136/jmg.2009.069732)

[6. (Wang2018Novel) Jiaping Wang, Qingping Zhang, Yan Chen, Shujie Yu, Xiru Wu, Xinhua Bao, and Yongxin Wen. Novel mef2c point mutations in chinese patients with rett (−like) syndrome or non-syndromic intellectual disability: insights into genotype-phenotype correlation. BMC Medical Genetics, October 2018. URL: http://dx.doi.org/10.1186/s12881-018-0699-1, doi:10.1186/s12881-018-0699-1. This article has 25 citations and is from a peer-reviewed journal.](https://doi.org/10.1186/s12881-018-0699-1)

[7. (Dong2017Myocyte) Chen Dong, Xue-Zhou Yang, Chen-Yan Zhang, Yang-Yang Liu, Ren-Bin Zhou, Qing-Di Cheng, Er-Kai Yan, and Da-Chuan Yin. Myocyte enhancer factor 2c and its directly-interacting proteins: a review. Progress in Biophysics and Molecular Biology, 126:22–30, July 2017. URL: http://dx.doi.org/10.1016/j.pbiomolbio.2017.02.002, doi:10.1016/j.pbiomolbio.2017.02.002. This article has 57 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.pbiomolbio.2017.02.002)

[8. (Sartorelli1997Molecular) Vittorio Sartorelli, Jing Huang, Yasuo Hamamori, and Larry Kedes. Molecular mechanisms of myogenic coactivation by p300: direct interaction with the activation domain of myod and with the mads box of mef2c. Molecular and Cellular Biology, 17(2):1010–1026, February 1997. URL: http://dx.doi.org/10.1128/mcb.17.2.1010, doi:10.1128/mcb.17.2.1010. This article has 302 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1128/mcb.17.2.1010)

[9. (Zweier2010Mutations) Markus Zweier, Anne Gregor, Christiane Zweier, Hartmut Engels, Heinrich Sticht, Eva Wohlleber, Emilia K. Bijlsma, Susan E. Holder, Martin Zenker, Eva Rossier, Ute Grasshoff, Diana S. Johnson, Lisa Robertson, Helen V. Firth, Cornelia Kraus, Arif B. Ekici, André Reis, and Anita Rauch. Mutations in mef2c from the 5q14.3q15 microdeletion syndrome region are a frequent cause of severe mental retardation and diminish mecp2 and cdkl5 expression. Human Mutation, 31(6):722–733, April 2010. URL: http://dx.doi.org/10.1002/humu.21253, doi:10.1002/humu.21253. This article has 149 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1002/humu.21253)

[10. (Molkentin1996Phosphorylation) Jeffery D. Molkentin, Li Li, and Eric N. Olson. Phosphorylation of the mads-box transcription factor mef2c enhances its dna binding activity. Journal of Biological Chemistry, 271(29):17199–17204, July 1996. URL: http://dx.doi.org/10.1074/jbc.271.29.17199, doi:10.1074/jbc.271.29.17199. This article has 95 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1074/jbc.271.29.17199)

[11. (Lu2018A) Cai-Xia Lu, Wei Wang, Qian Wang, Xing-Yuan Liu, and Yi-Qing Yang. A novel mef2c loss-of-function mutation associated with congenital double outlet right ventricle. Pediatric Cardiology, 39(4):794–804, February 2018. URL: http://dx.doi.org/10.1007/s00246-018-1822-y, doi:10.1007/s00246-018-1822-y. This article has 21 citations and is from a peer-reviewed journal.](https://doi.org/10.1007/s00246-018-1822-y)

[12. (Rocha2016MEF2C) Helena Rocha, Mafalda Sampaio, Ruben Rocha, Susana Fernandes, and Miguel Leão. Mef2c haploinsufficiency syndrome: report of a new mef2c mutation and review. European Journal of Medical Genetics, 59(9):478–482, September 2016. URL: http://dx.doi.org/10.1016/j.ejmg.2016.05.017, doi:10.1016/j.ejmg.2016.05.017. This article has 50 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.ejmg.2016.05.017)

[13. (Black1998TRANSCRIPTIONAL) Brian L. Black and Eric N. Olson. Transcriptional control of muscle development by myocyte enhancer factor-2 (mef2) proteins. Annual Review of Cell and Developmental Biology, 14(1):167–196, November 1998. URL: http://dx.doi.org/10.1146/annurev.cellbio.14.1.167, doi:10.1146/annurev.cellbio.14.1.167. This article has 834 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1146/annurev.cellbio.14.1.167)

[14. (Ghosh2009Physical) Tushar K. Ghosh, Fei Fei Song, Elizabeth A. Packham, Sarah Buxton, Thelma E. Robinson, Jonathan Ronksley, Tim Self, Andrew J. Bonser, and J. David Brook. Physical interaction between tbx5 and mef2c is required for early heart development. Molecular and Cellular Biology, 29(8):2205–2218, April 2009. URL: http://dx.doi.org/10.1128/mcb.01923-08, doi:10.1128/mcb.01923-08. This article has 103 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1128/mcb.01923-08)

[15. (Xu2015Transcription) Zhenhua Xu, Takeshi Yoshida, Lijuan Wu, Debasish Maiti, Liudmila Cebotaru, and Elia J. Duh. Transcription factor mef2c suppresses endothelial cell inflammation via regulation of nf‐κb and klf2. Journal of Cellular Physiology, 230(6):1310–1320, February 2015. URL: http://dx.doi.org/10.1002/jcp.24870, doi:10.1002/jcp.24870. This article has 50 citations and is from a peer-reviewed journal.](https://doi.org/10.1002/jcp.24870)