MECP2
Encyclopedia
MECP2 is a gene
that provides instructions for making its protein
product, MECP2, also referred to as MeCP2. MECP2 appears to be essential for the normal function of nerve cells. The protein seems to be particularly important for mature nerve cells, where it is present in high levels. The MeCP2 protein is likely to be involved in turning off ("repressing" or "silencing
") several other genes. This prevents the genes from making proteins when they are not needed. Recent work has shown that MeCP2 can also activate other genes. The MECP2 gene is located on the long (q) arm of the X chromosome
in band 28 ("Xq28"), from base pair
152,808,110 to base pair 152,878,611.
DNA methylation
is the major modification of eukaryotic genomes and plays an essential role in mammalian development. Human proteins MECP2 (this protein), MBD1
, MBD2
, MBD3
, and MBD4
comprise a family of nuclear proteins related by the presence in each of a methyl-CpG binding domain (MBD). Each of these proteins, with the exception of MBD3, is capable of binding specifically to methylated DNA. MECP2, MBD1 and MBD2 can also repress transcription from methylated gene promoters. In contrast to other MBD family members, MECP2 is X-linked and subject to X inactivation. MECP2 is dispensible in stem cells. MECP2 gene mutations are the cause of most cases of Rett syndrome
, a progressive neurologic developmental disorder and one of the most common causes of mental retardation in females.
s in the body, including the brain
, acting as a transcriptional repressor and activator, depending on the context. However, the idea that MeCP2 functions as an activator is relatively new and remains controversial. In the brain, it is found in high concentrations in neuron
s and is associated with maturation of the central nervous system
(CNS) and in forming synaptic contacts
.
that have been methylated. The MeCP2 protein then interacts with other proteins to form a complex that turns off the gene. Methylation
is a chemical alteration made to a "cytosine
" (C) when it occurs in a particular DNA sequence, "CpG
". Many genes have CpG island
s, which frequently occur near the beginning of the gene. MECP2 does not bind to these islands in most cases, as they are not methylated. The expression
of a few genes may be regulated through methylation of their CpG island, and MECP2 may play a role in a subset of these. Researchers have not yet determined which genes are targeted by the MeCP2 protein, but such genes are probably important for the normal function of the central nervous system. However, the first large-scale mapping of MECP2 binding sites in neurons found that only 6% of the binding sites are in CpG islands, and that 63% of MECP2-bound promoters are actively expressed and only 6% are highly methylated, indicating that MECP2's main function is something other than silencing methylated promoters.
Once bound, MeCP2 will condense the chromatin
structure, form a complex with histone deacetylase
s (HDAC), or block transcription factors directly. More recent studies have demonstrated that MeCP2 may also function as a transcriptional activator, through recruiting the transcription factor CREB1. This was an unexpected finding which suggests that MeCP2 is a key transcriptional regulator with potentially dual roles in gene expression. In fact, the majority of genes that are regulated by MeCP2 appear to be activated rather than repressed. However, it remains controversial whether MeCP2 regulates these genes directly or whether these changes are secondary in nature. Further studies have shown MeCP2 may be able to bind directly to un-methylated DNA in some instances. MeCP2 has been implicated in regulation of imprinted genes and loci that include UBE3A
and DLX5
.
The MBD domain forms a wedge and attaches to the methylated CpG sites on the DNA strands. The TRD region then reacts with SIN3A to recruit histone deacetylases (HDAC). There are also unusual, repetitive sequences found at the carboxyl terminus. This region is closely related to the fork head family, at the amino acid level.
is caused by mutations in the MECP2 gene. Several types of mutations have been identified in people with Rett syndrome. These mutations include changes in single base pairs (the building material of DNA), insertions or deletions of DNA in the gene, and changes that affect how the gene is processed into a protein. Mutations in the gene alter the structure of the MeCP2 protein or lead to reduced amounts of the protein. As a result, the protein is unable to bind to DNA or turn other genes on or off. Genes that are normally repressed by MeCP2 remain active and continue to make large amounts of particular proteins when they are not needed. Other genes that are normally activated by MeCP2 remain inactive and thus unable to make protein products. This defect probably disrupts the normal functioning of nerve cells, leading to the signs and symptoms of Rett syndrome.
This disease is mainly found in girls with a prevalence
of around 1 in every 10,000. Patients are born with very hard to find signs of a disorder, but after about six months to a year and half, speech and motor function capabilities start to decrease. This is followed by seizure
s, growth retardation and cognitive and motor impairment. This is a X-linked dominant
disease that is found predominantly affecting the paternal X chromosome. It has been linked to male lethality, due to its prevalence in females, but in rare cases some males can also be affected by Rett Syndrome.
Mutations in the MECP2 gene have also been identified in people with several other disorders affecting the central nervous system. For example, MECP2 mutations are associated with some cases of moderate to severe X-linked mental retardation. Mutations in the gene have also been found in males with severe brain dysfunction (neonatal encephalopathy) who live only into early childhood. In addition, several people with features of both Rett syndrome and Angelman syndrome
(a condition characterized by mental retardation, problems with movement, and inappropriate laughter and excitability) have mutations in the MECP2 gene. Lastly, MECP2 mutations or changes in the gene's activity have been reported in some cases of autism
(a developmental disorder that affects communication and social interaction).
More recent studies reported genetic polymorphisms in the MeCP2 genes in patients with systemic lupus erythematosus
(SLE). SLE is a systemic autoimmune disease that can affect multiple organs. MeCP2 polymorphisms have been reported so far in European-derived and Asian lupus patients.
The genetic loss of MECP2 has been identified as changing the properties of cells in the locus ceruleus
the exclusive source of noradrenergic innervation to the cerebral cortex
and hippocampus
.
Researchers have concluded that "Because these neurons are a pivotal source of norepinephrine throughout the brainstem and forebrain and are involved in the regulation of diverse functions disrupted in Rett syndrome, such as respiration and cognition, we hypothesize that the locus ceruleus is a critical site at which loss of MECP2 results in CNS dysfunction."
with SKI protein
and Nuclear receptor co-repressor 1
. In neuronal cells the MECP2 mRNA is thought to interact with miR-132, which silences the expression of the protein. This forms part of a homeostatic mechanism that could regulate MECP2 levels in the brain.
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
that provides instructions for making its protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
product, MECP2, also referred to as MeCP2. MECP2 appears to be essential for the normal function of nerve cells. The protein seems to be particularly important for mature nerve cells, where it is present in high levels. The MeCP2 protein is likely to be involved in turning off ("repressing" or "silencing
Gene silencing
Gene silencing is a general term describing epigenetic processes of gene regulation. The term gene silencing is generally used to describe the "switching off" of a gene by a mechanism other than genetic modification...
") several other genes. This prevents the genes from making proteins when they are not needed. Recent work has shown that MeCP2 can also activate other genes. The MECP2 gene is located on the long (q) arm of the X chromosome
X chromosome
The X chromosome is one of the two sex-determining chromosomes in many animal species, including mammals and is common in both males and females. It is a part of the XY sex-determination system and X0 sex-determination system...
in band 28 ("Xq28"), from base pair
Base pair
In molecular biology and genetics, the linking between two nitrogenous bases on opposite complementary DNA or certain types of RNA strands that are connected via hydrogen bonds is called a base pair...
152,808,110 to base pair 152,878,611.
DNA methylation
DNA methylation
DNA methylation is a biochemical process that is important for normal development in higher organisms. It involves the addition of a methyl group to the 5 position of the cytosine pyrimidine ring or the number 6 nitrogen of the adenine purine ring...
is the major modification of eukaryotic genomes and plays an essential role in mammalian development. Human proteins MECP2 (this protein), MBD1
MBD1
Methyl-CpG-binding domain protein 1 is a protein that in humans is encoded by the MBD1 gene. The protein encoded by MBD1 binds to methylated sequences in DNA, and thereby influences transcription. It binds to a variety of methylated sequences, and appears to mediate repression of gene expression...
, MBD2
Methyl-CpG-binding domain protein 2
Methyl-CpG-binding domain protein 2 is a protein that in humans is encoded by the MBD2 gene.-Interactions:Methyl-CpG-binding domain protein 2 has been shown to interact with HDAC1, Histone deacetylase 2, SIN3A, MIZF, MBD3 and GATAD2B....
, MBD3
MBD3
Methyl-CpG-binding domain protein 3 is a protein that in humans is encoded by the MBD3 gene.-Interactions:MBD3 has been shown to interact with Aurora A kinase, HDAC1, Methyl-CpG-binding domain protein 2, MTA2 and GATAD2B.-Further reading:...
, and MBD4
MBD4
Methyl-CpG-binding domain protein 4 is a protein that in humans is encoded by the MBD4 gene.-Interactions:MBD4 has been shown to interact with MLH1 and FADD.-Further reading:...
comprise a family of nuclear proteins related by the presence in each of a methyl-CpG binding domain (MBD). Each of these proteins, with the exception of MBD3, is capable of binding specifically to methylated DNA. MECP2, MBD1 and MBD2 can also repress transcription from methylated gene promoters. In contrast to other MBD family members, MECP2 is X-linked and subject to X inactivation. MECP2 is dispensible in stem cells. MECP2 gene mutations are the cause of most cases of Rett syndrome
Rett syndrome
Rett syndrome is a neurodevelopmental disorder of the grey matter of the brain that almost exclusively affects females. The clinical features include small hands and feet and a deceleration of the rate of head growth . Repetitive hand movements, such as wringing and/or repeatedly putting hands into...
, a progressive neurologic developmental disorder and one of the most common causes of mental retardation in females.
Function
MeCP2 protein is found in all cellCell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
s in the body, including the brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
, acting as a transcriptional repressor and activator, depending on the context. However, the idea that MeCP2 functions as an activator is relatively new and remains controversial. In the brain, it is found in high concentrations in neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
s and is associated with maturation of the central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
(CNS) and in forming synaptic contacts
Chemical synapse
Chemical synapses are specialized junctions through which neurons signal to each other and to non-neuronal cells such as those in muscles or glands. Chemical synapses allow neurons to form circuits within the central nervous system. They are crucial to the biological computations that underlie...
.
Mechanism of action
The MeCP2 protein binds to forms of DNADNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
that have been methylated. The MeCP2 protein then interacts with other proteins to form a complex that turns off the gene. Methylation
Methylation
In the chemical sciences, methylation denotes the addition of a methyl group to a substrate or the substitution of an atom or group by a methyl group. Methylation is a form of alkylation with, to be specific, a methyl group, rather than a larger carbon chain, replacing a hydrogen atom...
is a chemical alteration made to a "cytosine
Cytosine
Cytosine is one of the four main bases found in DNA and RNA, along with adenine, guanine, and thymine . It is a pyrimidine derivative, with a heterocyclic aromatic ring and two substituents attached . The nucleoside of cytosine is cytidine...
" (C) when it occurs in a particular DNA sequence, "CpG
CpG
CpG can be:*CpG site - methylated sequences of DNA significant in gene regulation*CpG Oligodeoxynucleotide - unmethylated sequences of DNA that have immunostimulatory properties*CpG island - regions of DNA that contain several CpG sites...
". Many genes have CpG island
CpG island
In genetics, CpG islands or CG islands are genomic regions that contain a high frequency of CpG sites but to date objective definitions for CpG islands are limited. In mammalian genomes, CpG islands are typically 300-3,000 base pairs in length. They are in and near approximately 40% of promoters of...
s, which frequently occur near the beginning of the gene. MECP2 does not bind to these islands in most cases, as they are not methylated. The expression
Gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...
of a few genes may be regulated through methylation of their CpG island, and MECP2 may play a role in a subset of these. Researchers have not yet determined which genes are targeted by the MeCP2 protein, but such genes are probably important for the normal function of the central nervous system. However, the first large-scale mapping of MECP2 binding sites in neurons found that only 6% of the binding sites are in CpG islands, and that 63% of MECP2-bound promoters are actively expressed and only 6% are highly methylated, indicating that MECP2's main function is something other than silencing methylated promoters.
Once bound, MeCP2 will condense the chromatin
Chromatin
Chromatin is the combination of DNA and proteins that make up the contents of the nucleus of a cell. The primary functions of chromatin are; to package DNA into a smaller volume to fit in the cell, to strengthen the DNA to allow mitosis and meiosis and prevent DNA damage, and to control gene...
structure, form a complex with histone deacetylase
Histone deacetylase
Histone deacetylases are a class of enzymes that remove acetyl groups from an ε-N-acetyl lysine amino acid on a histone. This is important because DNA is wrapped around histones, and DNA expression is regulated by acetylation and de-acetylation. Its action is opposite to that of histone...
s (HDAC), or block transcription factors directly. More recent studies have demonstrated that MeCP2 may also function as a transcriptional activator, through recruiting the transcription factor CREB1. This was an unexpected finding which suggests that MeCP2 is a key transcriptional regulator with potentially dual roles in gene expression. In fact, the majority of genes that are regulated by MeCP2 appear to be activated rather than repressed. However, it remains controversial whether MeCP2 regulates these genes directly or whether these changes are secondary in nature. Further studies have shown MeCP2 may be able to bind directly to un-methylated DNA in some instances. MeCP2 has been implicated in regulation of imprinted genes and loci that include UBE3A
UBE3A
Ubiquitin-protein ligase E3A also known as E6AP ubiquitin-protein ligase is an enzyme that in humans is encoded by the UBE3A gene. This enzyme is involved in targeting proteins for degradation within cells...
and DLX5
Dlx (gene)
Dlx is a family of homeodomain transcription factors which are related to the Drosophila distal-less gene .The family has been related to a number of developmental features.The family seems to be well preserved across species....
.
Structure
MeCP2 is part of a family of methyl-CpG-binding domain proteins (MBD), but possesses its own unique differences which help set it apart from the group. It has two functional domains:- a methyl-cytosineCytosineCytosine is one of the four main bases found in DNA and RNA, along with adenine, guanine, and thymine . It is a pyrimidine derivative, with a heterocyclic aromatic ring and two substituents attached . The nucleoside of cytosine is cytidine...
-binding domain (MBD) composed of 85 amino acidAmino acidAmino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
s; and - a transcriptional repression domain (TRD) composed of 104 amino acids
The MBD domain forms a wedge and attaches to the methylated CpG sites on the DNA strands. The TRD region then reacts with SIN3A to recruit histone deacetylases (HDAC). There are also unusual, repetitive sequences found at the carboxyl terminus. This region is closely related to the fork head family, at the amino acid level.
Role in disease
Rett syndromeRett syndrome
Rett syndrome is a neurodevelopmental disorder of the grey matter of the brain that almost exclusively affects females. The clinical features include small hands and feet and a deceleration of the rate of head growth . Repetitive hand movements, such as wringing and/or repeatedly putting hands into...
is caused by mutations in the MECP2 gene. Several types of mutations have been identified in people with Rett syndrome. These mutations include changes in single base pairs (the building material of DNA), insertions or deletions of DNA in the gene, and changes that affect how the gene is processed into a protein. Mutations in the gene alter the structure of the MeCP2 protein or lead to reduced amounts of the protein. As a result, the protein is unable to bind to DNA or turn other genes on or off. Genes that are normally repressed by MeCP2 remain active and continue to make large amounts of particular proteins when they are not needed. Other genes that are normally activated by MeCP2 remain inactive and thus unable to make protein products. This defect probably disrupts the normal functioning of nerve cells, leading to the signs and symptoms of Rett syndrome.
This disease is mainly found in girls with a prevalence
Prevalence
In epidemiology, the prevalence of a health-related state in a statistical population is defined as the total number of cases of the risk factor in the population at a given time, or the total number of cases in the population, divided by the number of individuals in the population...
of around 1 in every 10,000. Patients are born with very hard to find signs of a disorder, but after about six months to a year and half, speech and motor function capabilities start to decrease. This is followed by seizure
Seizure
An epileptic seizure, occasionally referred to as a fit, is defined as a transient symptom of "abnormal excessive or synchronous neuronal activity in the brain". The outward effect can be as dramatic as a wild thrashing movement or as mild as a brief loss of awareness...
s, growth retardation and cognitive and motor impairment. This is a X-linked dominant
Dominance relationship
Dominance in genetics is a relationship between two variant forms of a single gene, in which one allele masks the effect of the other in influencing some trait. In the simplest case, if a gene exists in two allelic forms , three combinations of alleles are possible: AA, AB, and BB...
disease that is found predominantly affecting the paternal X chromosome. It has been linked to male lethality, due to its prevalence in females, but in rare cases some males can also be affected by Rett Syndrome.
Mutations in the MECP2 gene have also been identified in people with several other disorders affecting the central nervous system. For example, MECP2 mutations are associated with some cases of moderate to severe X-linked mental retardation. Mutations in the gene have also been found in males with severe brain dysfunction (neonatal encephalopathy) who live only into early childhood. In addition, several people with features of both Rett syndrome and Angelman syndrome
Angelman syndrome
Angelman syndrome is a neuro-genetic disorder characterized by intellectual and developmental delay, sleep disturbance, seizures, jerky movements , frequent laughter or smiling, and usually a happy demeanor....
(a condition characterized by mental retardation, problems with movement, and inappropriate laughter and excitability) have mutations in the MECP2 gene. Lastly, MECP2 mutations or changes in the gene's activity have been reported in some cases of autism
Autism
Autism is a disorder of neural development characterized by impaired social interaction and communication, and by restricted and repetitive behavior. These signs all begin before a child is three years old. Autism affects information processing in the brain by altering how nerve cells and their...
(a developmental disorder that affects communication and social interaction).
More recent studies reported genetic polymorphisms in the MeCP2 genes in patients with systemic lupus erythematosus
Systemic lupus erythematosus
Systemic lupus erythematosus , often abbreviated to SLE or lupus, is a systemic autoimmune disease that can affect any part of the body. As occurs in other autoimmune diseases, the immune system attacks the body's cells and tissue, resulting in inflammation and tissue damage...
(SLE). SLE is a systemic autoimmune disease that can affect multiple organs. MeCP2 polymorphisms have been reported so far in European-derived and Asian lupus patients.
The genetic loss of MECP2 has been identified as changing the properties of cells in the locus ceruleus
Locus ceruleus
The locus coeruleus , is a nucleus in the brainstem involved with physiological responses to stress and panic. It was discovered in the 18th century by Félix Vicq-d'Azyr....
the exclusive source of noradrenergic innervation to the cerebral cortex
Cerebral cortex
The cerebral cortex is a sheet of neural tissue that is outermost to the cerebrum of the mammalian brain. It plays a key role in memory, attention, perceptual awareness, thought, language, and consciousness. It is constituted of up to six horizontal layers, each of which has a different...
and hippocampus
Hippocampus
The hippocampus is a major component of the brains of humans and other vertebrates. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Humans and other mammals have two hippocampi, one in...
.
Researchers have concluded that "Because these neurons are a pivotal source of norepinephrine throughout the brainstem and forebrain and are involved in the regulation of diverse functions disrupted in Rett syndrome, such as respiration and cognition, we hypothesize that the locus ceruleus is a critical site at which loss of MECP2 results in CNS dysfunction."
Interactions
MECP2 has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with SKI protein
SKI protein
The Ski protein is a nuclear protooncoprotein that is associated with tumors at high cellular concentrations. Ski has been shown to interfere with normal cellular functioning by both directly impeding expression of certain genes inside the nucleus of the cell as well as disrupting signaling...
and Nuclear receptor co-repressor 1
Nuclear receptor co-repressor 1
The nuclear receptor co-repressor 1 also known as thyroid-hormone- and retinoic-acid-receptor-associated co-repressor 1 is a protein that in humans is encoded by the NCOR1 gene....
. In neuronal cells the MECP2 mRNA is thought to interact with miR-132, which silences the expression of the protein. This forms part of a homeostatic mechanism that could regulate MECP2 levels in the brain.