HOME

TheInfoList



OR:

In the field of
molecular biology Molecular biology is the branch of biology that seeks to understand the molecular basis of biological activity in and between cells, including biomolecular synthesis, modification, mechanisms, and interactions. The study of chemical and physi ...
, myocyte enhancer factor-2 (Mef2) proteins are a family of
transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fun ...
s which through control of
gene expression Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product that enables it to produce end products, protein or non-coding RNA, and ultimately affect a phenotype, as the final effect. The ...
are important regulators of
cellular differentiation Cellular differentiation is the process in which a stem cell alters from one type to a differentiated one. Usually, the cell changes to a more specialized type. Differentiation happens multiple times during the development of a multicellular ...
and consequently play a critical role in embryonic
development Development or developing may refer to: Arts *Development hell, when a project is stuck in development *Filmmaking, development phase, including finance and budgeting *Development (music), the process thematic material is reshaped *Photographi ...
. In adult organisms, Mef2 proteins mediate the stress response in some tissues. Mef2 proteins contain both
MADS-box The MADS box is a conserved sequence motif. The genes which contain this motif are called the MADS-box gene family. The MADS box encodes the DNA-binding MADS domain. The MADS domain binds to DNA sequences of high similarity to the motif CC /Tsub>6G ...
and Mef2
DNA-binding domain A DNA-binding domain (DBD) is an independently folded protein domain that contains at least one structural motif that recognizes double- or single-stranded DNA. A DBD can recognize a specific DNA sequence (a recognition sequence) or have a genera ...
s.


Discovery

Mef2 was originally identified as a transcription factor complex through promoter analysis of the muscle
creatine kinase Creatine kinase (CK), also known as creatine phosphokinase (CPK) or phosphocreatine kinase, is an enzyme () expressed by various tissues and cell types. CK catalyses the conversion of creatine and uses adenosine triphosphate (ATP) to create phosp ...
(mck)
gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
to identify nuclear factors interacting with the mck enhancer region during muscle differentiation. Three human mRNA coding sequences designated RSRF (Related to
Serum Response Factor Serum response factor, also known as SRF, is a transcription factor protein. Function Serum response factor is a member of the MADS (MCM1, Agamous, Deficiens, and SRF) box superfamily of transcription factors. This protein binds to the serum ...
) were cloned and shown to dimerize, bind a consensus sequence similar to the one present in the MCK enhancer region, and drive transcription. RSRFs were subsequently demonstrated to encode human genes now named Mef2A, Mef2B and Mef2D.


Species distribution

The Mef2 gene is widely expressed in all branches of
eukaryote Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bact ...
s from
yeast Yeasts are eukaryotic, single-celled microorganisms classified as members of the fungus kingdom. The first yeast originated hundreds of millions of years ago, and at least 1,500 species are currently recognized. They are estimated to constitut ...
to humans. While Drosophila has a single Mef2 gene,
vertebrate Vertebrates () comprise all animal taxon, taxa within the subphylum Vertebrata () (chordates with vertebral column, backbones), including all mammals, birds, reptiles, amphibians, and fish. Vertebrates represent the overwhelming majority of the ...
s have at least four versions of the Mef2 gene (human versions are denoted as
MEF2A Myocyte-specific enhancer factor 2A is a protein that in humans is encoded by the ''MEF2A'' gene. MEF2A is a transcription factor in the Mef2 family. In humans it is located on chromosome 15q26. Certain mutations in MEF2A cause an autosomal d ...
, MEF2B,
MEF2C Myocyte-specific enhancer factor 2C also known as MADS box transcription enhancer factor 2, polypeptide C is a protein that in humans is encoded by the ''MEF2C'' gene. MEF2C is a transcription factor in the Mef2 family. Genomics The gene is l ...
, and
MEF2D Myocyte-specific enhancer factor 2D is a protein that in humans is encoded by the ''MEF2D'' gene. Interactions MEF2D has been shown to interact with: * CABIN1, * EP300, * MAPK7, * Myocyte-specific enhancer factor 2A, * NFATC2 * Sp1 transcript ...
), all expressed in distinct but overlapping patterns during embryogenesis through adulthood.


Sequence and structure

All of the mammalian Mef2 genes share approximately 50% overall amino acid identity and about 95% similarity throughout the highly conserved
N-terminal The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the am ...
MADS-box and Mef2 domains, however their sequences diverge in their
C-terminal The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain ( protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...
transactivation domain (see figure to the right). The MADS-box serves as the minimal DNA-binding domain, however an adjacent 29-amino acid extension called the Mef2 domain is required for high affinity DNA-binding and dimerization. Through an interaction with the MADS-box, Mef2 transcription factors have the ability to homo- and heterodimerize, and a classic nuclear localization sequence ( NLS) in the C-terminus of Mef2A, -C, and – D ensures nuclear localization of the protein. D-Mef2 and human MEF2B lack this conserved NLS but are still found in the nucleus.


Function


Development

In ''Drosophila'', Mef2 regulates muscle development. Mammalian Mef2 can cooperate with bHLH transcription factors to turn non-muscle cells in culture into muscle. bHLH factors can activate Mef2c expression, which then acts to maintain its own expression. Loss of Mef2c in
neural crest Neural crest cells are a temporary group of cells unique to vertebrates that arise from the embryonic ectoderm germ layer, and in turn give rise to a diverse cell lineage—including melanocytes, craniofacial cartilage and bone, smooth muscle, pe ...
cells results in
craniofacial Craniofacial (''cranio-'' combining form meaning head or skull + ''-facial'' combining form referring to the facial structures grossly) is an adjective referring to the parts of the head enclosing the brain and the face. The term is typically used ...
defects in the developing embryo and neonatal death caused by blocking of the upper airway passages. Mef2c upregulates the expression of the
homeodomain A homeobox is a DNA sequence, around 180 base pairs long, that regulates large-scale anatomical features in the early stages of embryonic development. For instance, mutations in a homeobox may change large-scale anatomical features of the full-g ...
transcription factors
DLX5 Homeobox protein DLX-5 is a protein that in humans is encoded by the distal-less homeobox 5 gene, or ''DLX5'' gene. DLX5 is a member of DLX gene family. Function This gene encodes a member of a homeobox transcription factor gene family simila ...
and
DLX6 Homeobox protein DLX-6 is a protein that in humans is encoded by the ''DLX6'' gene. This gene encodes a member of a homeobox transcription factor gene family similar to the Drosophila ''Drosophila'' () is a genus of flies, belonging to the ...
, two transcription factors that are necessary for craniofacial development.


Stress response

In adult tissues, Mef2 proteins regulate the stress-response during
cardiac hypertrophy Ventricular hypertrophy (VH) is thickening of the walls of a ventricle (lower chamber) of the heart. Although left ventricular hypertrophy (LVH) is more common, right ventricular hypertrophy (RVH), as well as concurrent hypertrophy of both ventr ...
and tissue remodeling in cardiac and skeletal muscle.


Cardiovascular system

Mef2 is a critical regulator in heart development and cardiac gene expression. In vertebrates, there are four genes in the Mef2 transcription factor family: Mef2a, Mef2b, Mef2c, and Mef2d. Each is expressed at specific times during development. Mef2c, the first gene to be expressed in the heart, is necessary for the development of the anterior (secondary) heart field (AHF), which helps to form components of the cardiac outflow tract and most of the right ventricle. In addition, Mef2 genes are indicated in activating gene expression to aid in sprouting angiogenesis, the formation of new blood vessels from existing vessels.


Knockout studies

In mice, knockout studies of Mef2c have demonstrated that crucial role that it plays in heart development. Mice without the Mef2c die during embryonic day 9.5–10 with major heart defects, including improper looping, outflow tract abnormalities, and complete lack of the right ventricle. This indicates improper differentiation of the anterior heart field. When Mef2c is knocked out specifically in the AHF, the mice die at birth with a range of outflow tract defects and severe cyanosis. Thus, Mef2 is necessary for many aspects of heart development, specifically by regulating the anterior heart field.Barnes RM, Harris IS, Jaehnig EJ, Sauls K, Sinha T, Rojas A, Schachterle W, McCulley DJ, Norris RA, Black BL. (January 2016). "Mef2c regulates outflow tract alignment and transcriptional control of Tdgf1." Development. 143: 774-779. oi:10.1242/dev.126383


Additional Information

MEF2, Myocyte Enhancer Factor 2, is a transcription factor with four specific numbers such as MEF2A, B, C, and D. Each MEF2 gene is located on a specific chromosome. MEF2 is known to be involved in the development and the looping of the heart (Chen) MEF2 is necessary for myocyte differentiation and gene activation (Black). Both roles contribute to the heart structure, and if there is a disruption with MEF2 in embryonic development, it can lead to two phenotypic problems (Karamboulas). The Type-I phenotype can cause severe malformations to the heart and the type-II phenotype, while it looks normal, has a thin-walled myocardium which can cause cardiac insufficiency. Another problem that can arise is from the knockout gene MEF2C. MEF2C is known to be directly related to congenital heart disease when associated with Tdgf1 (teratocarcinoma-derived growth factor 1). If MEF2C improperly regulates Tdgf1, developmental defects arise, especially within the embryonic development of the heart. (Chen). The way that MEF2C interacts with the protein Tdgf1 is through the 〖Ca〗^(2+) signaling pathway, which is required to regulate different mechanisms. MicroRNA’s, non-small coding RNAs, also play a specific role in regulating MEF2C. The expression of congenital heart disease is upregulated due to the downregulation of the microRNA miR-29C (Chen). A few other known diseases associated with the MEF2 family are liver fibrosis, cancers, and neurodegenerative diseases (Chen).


References

Black, Brian L., and Richard M. Cripps. “Myocyte Enhancer Factor 2 Transcription Factors in Heart Development and Disease.” Heart Development and Regeneration, 2010, pp. 673–699., doi:10.1016/b978-0-12-381332-9.00030-x. Chen, Xiao, et al. “MEF2 Signaling and Human Diseases.” Oncotarget, vol. 8, no. 67, 2017, pp. 112152–112165., doi:10.18632/oncotarget.22899. Karamboulas, C., et al. “Disruption of MEF2 Activity in Cardiomyoblasts Inhibits Cardiomyogenesis.” Journal of Cell Science, vol. 120, no. 1, 2006, pp. 4315–4318., doi:10.1242/jcs.03369.


External links


OrthoDB
Orthology in all Eukaryotes * * * * * {{Transcription factors, g4 Drosophila melanogaster genes Transcription factors