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FLASH GENE

Symbol

MECP2

contributors: mct/pgu/shn - updated : 01-02-2017

HGNC name	methyl CpG binding protein 2 (Rett syndrome)
HGNC id	6990

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

PROTEIN

PHYSICAL PROPERTIES		basic
STRUCTURE

motifs/domains	N-terminal methylated DNA-binding domain
	a methyl-CpG-binding (MBD) and a central transcription regulation domain
	a nuclear localization signal (NLS) reported to reside between amino acids 255-271
	a transcriptional repression (TRD) domains, repressing the MAGEA1, MAGEA2, MAGEA3, MAGEA12 promoters and corepressor interacting region
	three AT-hook-like domains over a stretch of 250 AAs, like HMGA DNA-bending proteins, and the AT-Hook 2 domain is important for chromatin maintenance and ATRX localization
	(r)GPR(k) motifs and SPKK motifs that have been found to bind to minor groove of at-rich DNA
	C terminal segment with WW domain binding region
	of unknown function

HOMOLOGY

interspecies	ortholog to Mecp2, Mus musculus
	ortholog to Mecp2, Rattus norvegicus
	ortholog to MECP2, Pan troglodytes
	ortholog to mecp2, Danio rerio

Homologene

FAMILY

CATEGORY

regulatory , DNA associated , transcription factor

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,nucleus,nucleoplasm
	intracellular,nucleus,chromatin/chromosome,heterochromosome

basic FUNCTION	involved in the regulation of gene expression (in normal neuronal maturation)
	selectivity binds 5'methyl cytosine residues in symmetrically positioned CpG dinucleotides, preferentially in the promoter regions of genes subject to transcriptional silencing after DNA methylation
	transcriptional repression either dependent on chromatin modification by histone deacetylation, or chromatin independent, not affecting imprinted gene expression in blood and brain
	may regulate the transcription of activity dependent genes in neuronal cells, which is important in synapse development and neuronal plasticity
	multifunctional corepressor of methylated genes, recruited on repressed promoters and associated with component of the SWI/SNF complex
	assembling novel secondary chromatin structures independent of DNA modification, may be silencing chromatin and involved in its organization
	multifunctional protein, playing a role as transcriptional repressor and also splicing regulator
	regulating UBE3A and GABRB3 in postnatal brain
	regulating splicing of reporter minigenes
	unlikely to be the CpG binding molecule that translates a methylation signal in imprinting
	natural inhibitor of the basic helix-loop-helix transcription factors and the retinoblastoma tumor suppressor protein
	modulating HP1 heterochromatin association during myogenic differentiation
	regulates the expression of a wide range of genes in the hypothalamus and that it can function as both an activator and a repressor of transcription
	silencing OF MECP2 and MBD1 appear to affect cellular processes independently and discrete sets of genes involved in cellular proliferation, apoptosis, invasion and migration are targeted by each protein
	MBD2 and MECP2 regulate distinct transitional stages of olfactory receptor neuron (ORN) differentiation
	plays a critical role in interpreting epigenetic signatures that command chromatin conformation and regulation of gene transcription
	can epigenetically regulate specific miRNAs in adult neural stem cells
	roles in the development and function of the mesolimbocortical dopamine circuit
	capable of influencing expression of genes associated with the D4Z4 repeat on chromosome 4
	binds cooperatively to its substrate and competes with histone H1 for chromatin binding sites
	is not essential for early wiring of the nervous system but instead may only be required at late stages
	critical for normal function of GABA-releasing neurons and subtle dysfunction of GABAergic neurons contributes to numerous neuropsychiatric phenotypes
	act as a DNA methylation-dependent transcriptional repressor, but may have additional roles in regulating gene expression and chromatin structure
	binds preferentially to methylated CpGs and regulates gene expression by causing changes in chromatin structure
	likely enhanced role for MECP2 in the aging brain
	role for MECP2 in the regulation of chromatin structure
	MECP2 shares likely a common ancestry with the HMGA family of proteins
	removal of MECP2 from gene promoters activates transcription
	clearly performs important functions besides classical transcriptional repression
	MECP2 and UBE3A play likely a role in the transcriptional control of common target gene expression
	potentially involved in cholesterol homeostasis
	MECP2 serves as a critical safeguard that confers Tregs with resilience against inflammation
	is a nuclear protein with important roles in regulating chromatin structure and gene expression
	is a multi-function factor involved in locus-specific transcriptional modulation and the regulation of genome architecture, e.g., pericentric heterochromatin (PCH) organization
	MECP2 and ATRX are reciprocally dependent both for their expression and targeting to chromocenters

CELLULAR PROCESS	nucleotide, transcription, regulation
	nucleotide, RNA splicing

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

a component	complexing with HDAC1, HDAC2
	complexing with biochemically defined nucleosomal arrays

INTERACTION

DNA	IkappaBalpha promoter via a methyl-CpG-dependent mechanism

RNA

small molecule	cofactor, other,
	methylated CpG dinucleotides
	binding of 5-hydroxymethylcytosine (5hmC) by MECP2 plays a central role in the epigenetic regulation of neural chromatin and gene expression

protein	mSin3, c-Ski and N-CoR
	HMGB1
	DNA (cytosine-5-)-methyltransferase 1, DNMT1
	PU.1
	Xenopus laevis protein of 20 kDa, p20
	Brahma, Brm
	cyclin-dependent kinase-like 5, CDKL5
	alpha thalassemia/mental retardation syndrome X-linked, ATRX
	target of DLX5
	HP1
	inner nuclear membrane lamin B receptor LBR
	SMARCA2 and SLC6A2
	YY1
	MECP2 and MBD2 direct interactions could crosslink chromatin fibers and therefore give novel insight into the molecular mechanism of MBD mediated global heterochromatin architecture
	HTT-MECP2 interactions are enhanced in the presence of the expanded polyglutamine (polyQ) tract and are stronger in the nucleus compared with the cytoplasm
	is critical to sustain FOXP3 expression in Tregs during inflammation
	RNF4 does not promote DNA demethylation, but mediates the ubiquitination of MECP2, a methyl-CpG-binding domain (MBD) protein
	MECP2 acts as a microglia-specific transcriptional repressor of SLC38A1
	PSIP1 is an autoantigen in prostate cancer that closely interacts with another 70kD dense fine speckled (DFS) nuclear protein, MECP2
	KPNA3 and KPNA4 are key binding partners of MECP2, and mediate the nuclear import of MECP2
	elevated NUDT21 increases usage of the distal polyadenylation site in the MECP2 3' UTR, resulting in an enrichment of inefficiently translated long mRNA isoforms
	memory associated WWC1 is a target of MECP2 in regulating dendritic growth

cell & other

REGULATION

Phosphorylated by

homeodomain-interacting protein kinase 2 , HIPK2

Other	target of DLX5 (dysregulation of DLX5 and LOI in mutations of Rett syndrome)
	precise control of MECP2 is critical for normal behavior and neurodevelopmental disorders will result from a subtle reduction in the expression
	phosphorylation of MECP2 modulates its dynamic function in neurons transiting between resting and active states within neural circuits that underlie behaviors
	MECP2 contains multiple posttranslational modifications, including phosphorylation, acetylation, and ubiquitylation

ASSOCIATED DISORDERS

corresponding disease(s)

RTT , RTTM , MRX28 , PPMX , MRXS31 , ESMR , DUPXQ28

related resource

RettBASE

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional germinal mutation       in sporadic RTT, mutation exclusively of paternal origin constitutional somatic mutation       somatic mosaicism in male (with classic RTT syndrome) constitutional   amplification     duplication in mental retardation in males constitutional germinal mutation       in autism sporadic, rare cases tumoral     --over   in cancer prostate cells constitutional     --other loss of function a 50p100 decrease in MECP2 levels might indeed cause disease, and misregulation may be a common feature of many neurodevelopmental disorders constitutional       loss of function neural cell fate and neuronal maintenance may be perturbed by senescence triggered by impaired MECP2 activity either before or after neural differentiation (

Susceptibility

to sporadic autism to reduced cortical surface area

Variant & Polymorphism other	common MECP2 haplotype associates with reduced cortical surface area

Candidate gene
Marker
Therapy target
	System Type Disorder Pubmed mental retardation other   a lower dosage of gentamicin was enough to increase full-length MECP2 levels in RTT neurons, rescuing glutamatergic synapses mental retardation other   various steps in the cholesterol pathway may be valid targets for treatment of Rett sdr

ANIMAL & CELL MODELS

	overexpression of MeCP2 in the mouse heart causes embryonic lethality with cardiac septum hypertrophy and dysregulated expression of MeCP2 in skeletal tissue produces severe malformations
	mice bearing a hypomorphic mutation in Mecp2 display altered behavioral responses to acute and repeated AMPH treatment and changes in both the development and plasticity of striatal synapses
	in globally MeCP2-deficient mice, re-expression of Mecp2 preferentially in astrocytes significantly improved locomotion and anxiety levels, restored respiratory abnormalities to a normal pattern, and greatly prolonged lifespan compared to globally null mice
	neuron-specific deletion of MeCP2 recapitulates the RTT symptoms of the whole-body KO mouse, implicating an essential role for MeCP2 in neurons
	decreased dopamine transmission due to heterogeneous Mecp2 expression contributes to the parkinsonian features of RTT in Mecp2(+/-) mice
	mutations occurring in Rett patients are defective in the chromatin architecture function of MeCP2
	cholesterol homeostasis is disrupted in Mecp2 mutant mice
	loss of MECP2 causes mislocalization of the ATRX in the hippocampus and cortex of symptomatic KO mice