Affinage

MECP2

Methyl-CpG-binding protein 2 · UniProt P51608

Round 2 corrected
Length
486 aa
Mass
52.4 kDa
Annotated
2026-04-28
130 papers in source corpus 35 papers cited in narrative 35 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MeCP2 is a chromatin-associated transcriptional regulator that interprets DNA methylation patterns to control gene expression in neurons and other cell types. Its methyl-CpG binding domain (MBD) recognizes symmetrically methylated CpG dinucleotides, non-CG methylation (mCAC), and hydroxymethylated DNA, targeting MeCP2 to heterochromatin and gene bodies genome-wide (PMID:1606614, PMID:25762136, PMID:33561390, PMID:34324427); its transcriptional repression domain (TRD/NID) physically bridges methylated DNA to the NCoR1/2–HDAC co-repressor complex, and this minimal interaction is sufficient for near-normal neurological function in mice (PMID:9620804, PMID:29019980, PMID:30463906). Beyond canonical repression, MeCP2 promotes transcription at CpG-rich promoters as a positive RNA Polymerase II co-factor (PMID:38697112), facilitates co-transcriptional splicing through recruitment of Tra2b (PMID:28480880), forms liquid-like heterochromatin condensates that compartmentalize chromatin regulators (PMID:32698189), and its activity is tuned by phosphorylation (Ser421, Ser80) and SUMOylation (K223, K412) (PMID:24671997, PMID:26842955). Loss-of-function mutations in MECP2 cause Rett syndrome (PMID:10508514).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1992 High

    Identification of MeCP2 as a protein that selectively binds single symmetrically methylated CpG sites and localizes to pericentromeric heterochromatin established the first direct physical reader of vertebrate DNA methylation marks.

    Evidence Protein purification from rat brain, cDNA cloning, immunofluorescence in mouse cells

    PMID:1606614

    Open questions at the time
    • No function assigned beyond DNA binding
    • Binding specificity for non-CG methylation unknown
  2. 1996 High

    Demonstration that the 85-amino-acid MBD is necessary and sufficient for heterochromatic targeting, and that DNA methylation is required in vivo, resolved how MeCP2 achieves locus-specific localization.

    Evidence MeCP2-LacZ fusion domain deletions in wild-type and methylation-deficient cells with immunofluorescence

    PMID:8524323

    Open questions at the time
    • Functional consequence of heterochromatin targeting not yet established
    • Contribution of non-MBD regions to localization not addressed
  3. 1998 High

    Discovery that MeCP2 represses methylated promoters through a defined transcriptional repression domain (TRD) that recruits the mSin3A–HDAC co-repressor complex linked DNA methylation to histone deacetylation and established MeCP2's primary enzymatic effector mechanism.

    Evidence In vitro transcription of methylated templates, GAL4-TRD fusion repression assays, co-immunoprecipitation of mSin3A/HDAC, trichostatin A rescue; independently confirmed in Xenopus oocyte chromatin system

    PMID:9038338 PMID:9620779 PMID:9620804

    Open questions at the time
    • Identity of specific HDAC isoforms mediating repression not resolved
    • Whether HDAC activity is required versus scaffolding was not distinguished
  4. 1999 High

    Mapping of MECP2 mutations in Rett syndrome patients to the MBD and TRD established loss of MeCP2 function as the molecular cause of this X-linked neurodevelopmental disorder.

    Evidence Systematic sequencing of MECP2 in RTT families identifying missense, frameshift, and nonsense mutations

    PMID:10508514

    Open questions at the time
    • Genotype–phenotype correlations for individual mutations not resolved
    • Why neurons are selectively vulnerable to MeCP2 loss was unknown
  5. 2002 High

    Finding that MeCP2 associates with histone H3K9 methyltransferase activity extended its effector repertoire beyond deacetylation, showing it can recruit multiple repressive chromatin modifications.

    Evidence Co-immunoprecipitation of HMT activity, in vitro HMT assay, ChIP at the H19 imprinting control region

    PMID:12427740

    Open questions at the time
    • Identity of the specific H3K9 methyltransferase not determined
    • Relative contribution of H3K9me versus deacetylation to repression unclear
  6. 2003 High

    Showing that neuronal depolarization releases MeCP2 from the Bdnf promoter linked MeCP2 to activity-dependent gene regulation, reframing it as a dynamic, signal-responsive repressor rather than a constitutive silencer.

    Evidence ChIP and bisulfite sequencing at Bdnf promoter III in depolarized cortical neurons

    PMID:14593184

    Open questions at the time
    • Mechanism of activity-dependent MeCP2 release (later shown to involve phosphorylation) not yet known
    • Genome-wide scope of activity-dependent derepression not addressed
  7. 2004 High

    Demonstration that MeCP2 mediates formation of a silent-chromatin loop at the imprinted Dlx5-Dlx6 locus revealed a higher-order chromatin architectural function for the protein.

    Evidence ChIP-loop assay and quantitative RT-PCR in Mecp2-null mouse brain

    PMID:15608638

    Open questions at the time
    • Generality of MeCP2-dependent looping across the genome not tested
    • Whether looping is direct or indirect through recruited factors not resolved
  8. 2011 High

    Inducible deletion of Mecp2 in adult mice recapitulated RTT-like phenotypes, establishing that MeCP2 provides ongoing maintenance of neuronal function rather than acting only during development.

    Evidence Tamoxifen-inducible Cre-lox conditional knockout in adult mice with behavioral phenotyping

    PMID:21636743

    Open questions at the time
    • Molecular targets disrupted acutely versus chronically not distinguished
    • Cell-type specificity of adult requirement not resolved
  9. 2012 High

    Identification of MeCP2 as the major 5-hydroxymethylcytosine (5hmC)-binding protein in brain, with the RTT mutation R133C selectively impairing 5hmC recognition, revealed a second epigenetic mark read by MeCP2 and a cell-type-specific regulatory mechanism.

    Evidence Genome-wide 5hmC/5mC mapping, affinity binding assays, R133C mutant binding analysis

    PMID:23260135

    Open questions at the time
    • Functional consequence of 5hmC versus 5mC binding on gene regulation not distinguished genome-wide
    • Crystal structure of MBD–5hmC complex not yet available
  10. 2013 High

    Discovery that intragenic DNA methylation recruits MeCP2 to alternatively spliced exons, promoting exon inclusion through HDAC-dependent histone hypoacetylation, extended MeCP2 function from transcriptional regulation to co-transcriptional splicing control.

    Evidence ChIP-seq for MeCP2 and histone marks, MeCP2 knockdown RNA-seq, HDAC inhibitor treatment showing overlapping exon-skipping events

    PMID:23938295

    Open questions at the time
    • Direct interaction with splicing machinery not yet shown
    • Relative contribution of splicing versus transcriptional defects to RTT phenotype unknown
  11. 2014 High

    Characterization of MeCP2 phosphorylation (Ser421) and SUMOylation (K223, K412) as functionally important post-translational modifications established how signal-dependent tuning of MeCP2's co-repressor interactions and chromatin occupancy enables dynamic gene control in neurons.

    Evidence Ser421Ala knock-in mice with behavioral and electrophysiological phenotyping; SUMOylation assays with PIAS1, phospho-site mutagenesis, Bdnf expression rescue in Mecp2 conditional KO mice

    PMID:24188180 PMID:24671997 PMID:26842955

    Open questions at the time
    • Quantitative stoichiometry of these modifications in vivo not determined
    • Whether PTMs regulate condensate behavior not tested
  12. 2015 High

    Genome-wide analyses revealing that MeCP2 preferentially represses long genes by binding methylated CA dinucleotides in gene bodies identified mCA as a key MeCP2 substrate and explained the neuronal specificity of RTT (mCA accumulates postnatally in neurons).

    Evidence RNA-seq in Mecp2 mutant mice and human RTT brain, MeCP2 ChIP-seq, rescue by suppression of long gene expression

    PMID:25762136

    Open questions at the time
    • Whether mCA binding and mCG binding are functionally separable in vivo not yet tested genetically
  13. 2017 High

    Genetic sufficiency experiments showed that a minimal MeCP2 retaining only the MBD and NCoR/SMRT interaction domain (NID) rescued near-normal neurological function, definitively establishing the MBD–NCoR bridge as MeCP2's core mechanism; concurrently, MeCP2 was shown to recruit splicing factor Tra2b and suppress intron retention genome-wide.

    Evidence MBD+NID minimal knock-in mice with behavioral phenotyping and AAV rescue; interactome mass spectrometry with RNA-seq of MeCP2-depleted tissues

    PMID:28480880 PMID:29019980

    Open questions at the time
    • Contributions of intervening disordered regions to condensate formation and genome-wide occupancy not captured by minimal-domain model
    • Direct structural basis of NID–NCoR interaction not determined
  14. 2018 High

    Biochemical demonstration that MeCP2's TRD directly binds and inhibits DNMT3A by stabilizing its autoinhibitory conformation identified MeCP2 as a feedback regulator of de novo DNA methylation, adding an upstream regulatory layer to its function.

    Evidence In vitro DNMT3A methyltransferase activity assay with purified proteins, co-IP, conformationally locked DNMT3A variants, global methylation measurement by mass spectrometry

    PMID:30102379

    Open questions at the time
    • In vivo physiological significance of DNMT3A inhibition not demonstrated in animal models
    • Whether this interaction is disrupted in RTT not tested
  15. 2018 High

    Epistatic analysis in MECP2 duplication syndrome models showed that overexpression toxicity is driven by excessive NCoR1/2 recruitment but is independent of HDAC3 catalytic activity, dissociating co-repressor scaffolding from histone deacetylase enzymatic function.

    Evidence Multiple knock-in mouse models expressing WT or mutant MeCP2 at 4× levels crossed with NCoR HDAC-activation-dead alleles; survival and behavioral endpoints

    PMID:30463906

    Open questions at the time
    • Which enzymatic activities recruited by NCoR (if not HDAC3) mediate toxicity not identified
    • Relevance to loss-of-function RTT not directly tested
  16. 2020 High

    Demonstration that MeCP2 forms liquid-like condensates stimulated by DNA, which selectively incorporate heterochromatin cofactors and are disrupted by RTT mutations, provided a biophysical mechanism for how MeCP2 compartmentalizes and concentrates repressive machinery at heterochromatin.

    Evidence Live-cell FRAP, in vitro droplet assays with purified MeCP2, co-partitioning of heterochromatin versus euchromatin factors, RTT mutation analysis

    PMID:32698189

    Open questions at the time
    • Whether condensate disruption is a primary driver of RTT pathology versus loss of NCoR recruitment not resolved
    • In vivo material properties of MeCP2 condensates not measured
  17. 2021 High

    MBD domain-swap knock-in mice that selectively lose mCAC recognition while retaining mCG binding developed severe RTT-like phenotypes, genetically proving that non-CG methylation reading is an essential, non-redundant function of MeCP2 in the brain; concurrent structural work revealed how Arg133 specifically recognizes 5hmC-modified CA repeats.

    Evidence MBD domain-swap knock-in mice with behavioral and transcriptomic analysis; crystal structure of MBD bound to hydroxymethylated CA repeat DNA with R133C mutation analysis

    PMID:33561390 PMID:34324427

    Open questions at the time
    • Relative contributions of mCAC versus hmCAC reading to neuronal gene regulation not separated
    • Whether mCAC reading drives condensate formation in vivo not tested
  18. 2024 High

    Discovery that MeCP2 directly interacts with RNA Polymerase II and acts as a positive transcriptional co-factor at >4,000 CpG-rich promoters in human neurons overturned the view of MeCP2 as a purely repressive factor and established a dual activator–repressor model.

    Evidence CUT&Tag for MeCP2 and RNA Pol II in human neurons, co-IP of MeCP2–Pol II, transcriptome and proteome analysis of RTT-mutant neurons

    PMID:38697112

    Open questions at the time
    • Mechanism by which MeCP2 promotes Pol II activity at promoters not defined
    • Whether activating function requires NCoR interaction or uses an independent domain not known
    • Reconciliation of positive and negative regulatory functions at the single-locus level not achieved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include how MeCP2's activating and repressive functions are partitioned at individual loci, whether condensate disruption is a primary pathogenic mechanism in RTT, the structural basis of the NID–NCoR interaction, and how post-translational modifications regulate condensate dynamics in vivo.
  • No structural model of full-length MeCP2 or MeCP2–NCoR complex
  • Quantitative PTM stoichiometry in vivo not determined
  • Causal role of condensate dysfunction in RTT pathology not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 6 GO:0140110 transcription regulator activity 5 GO:0042393 histone binding 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005634 nucleus 4 GO:0005694 chromosome 3 GO:0005654 nucleoplasm 1
Pathway
R-HSA-4839726 Chromatin organization 5 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-1643685 Disease 3 R-HSA-112316 Neuronal System 2 R-HSA-8953854 Metabolism of RNA 2
Partners
DNMT3AHDAC1NCOR1NCOR2PIAS1SIN3ATCF20TRA2B
Complex memberships
NCoR1/SMRT–HDAC co-repressor complexmSin3A–HDAC complex

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1992 MeCP2 was identified, purified, and cloned as a novel chromosomal protein that binds to DNA containing a single symmetrically methylated CpG dinucleotide; immunostaining showed it is concentrated in pericentromeric heterochromatin of mouse cells, paralleling the distribution of methyl-CpG. Protein purification, cDNA cloning, immunostaining/immunofluorescence Cell High 1606614
1996 DNA methylation specifies chromosomal localization of MeCP2 in vivo; the 85-amino-acid methyl-CpG binding domain (MBD) is necessary and sufficient for heterochromatic targeting, demonstrated by loss of localization in cells with reduced genomic methylation and by domain-deletion experiments. Transient expression of MeCP2-LacZ fusion proteins in wild-type and DNA methylation-deficient mutant cells; immunofluorescence localization Molecular and cellular biology High 8524323
1997 MeCP2 is an abundant nuclear transcriptional repressor; it represses transcription from methylated but not unmethylated promoters in vitro, contains a transcriptional repression domain (TRD) capable of long-range repression in vivo, and can displace histone H1 from preassembled methylated chromatin. In vitro transcription assay with methylated promoters, GAL4 fusion transient transfection in vivo repression assay, chromatin reconstitution/H1 displacement Cell High 9038338
1998 MeCP2 transcriptional repression involves histone deacetylase: MeCP2's transcription repression domain (TRD) associates with the corepressor mSin3A and histone deacetylases (HDAC); repression is relieved by the HDAC inhibitor trichostatin A, linking DNA methylation and histone deacetylation through MeCP2. Co-immunoprecipitation, in vivo repression assay with HDAC inhibitor trichostatin A Nature High 9620804
1998 In Xenopus oocytes, methylated DNA assembled into chromatin binds MeCP2, which co-fractionates with Sin3 and histone deacetylase; silencing by MeCP2 and methylated DNA is relieved by HDAC inhibition, establishing a direct causal link between DNA methylation-dependent silencing and chromatin modification via MeCP2. Xenopus oocyte chromatin assembly/transcription assay, co-fractionation, HDAC inhibitor treatment Nature genetics High 9620779
1999 Mutations in MECP2 (missense in the MBD, frameshift and nonsense disrupting the TRD) are the cause of Rett syndrome; MeCP2 mediates transcriptional repression through interaction with histone deacetylase and SIN3A, establishing loss-of-function MECP2 mutations as the molecular basis of RTT. Systematic gene screening, sequencing of patient samples; functional domain context inferred from known biochemistry Nature genetics High 10508514
2002 MeCP2 links DNA methylation to histone H3 Lys9 methylation: MeCP2 associates with histone methyltransferase activity in vivo, directed against H3-K9; two repression domains of MeCP2 tether this activity, and MeCP2 occupancy at the H19 differentially methylated domain coincides with increased H3-K9 methylation. Co-immunoprecipitation of histone methyltransferase activity, in vitro histone methyltransferase assay, chromatin immunoprecipitation (ChIP) The Journal of biological chemistry High 12427740
2003 Activity-dependent BDNF gene expression in neurons involves dissociation of a MeCP2-HDAC-mSin3A repressor complex from the Bdnf promoter region, accompanied by decreased CpG methylation; depolarization releases this repression, establishing MeCP2 as an activity-regulated transcriptional repressor at the Bdnf locus. Chromatin immunoprecipitation (ChIP), bisulfite sequencing, neuronal depolarization assay Science High 14593184
2004 MeCP2 mediates formation of a silent-chromatin 11-kb loop at the Dlx5-Dlx6 imprinted locus in mouse brain; MeCP2 recruits HDAC1 and promotes repressive H3-K9 methylation at this locus; in Mecp2-null brain, the loop is absent and Dlx5/Dlx6 transcription is approximately 2-fold elevated, indicating a chromatin looping mechanism for locus-specific gene regulation. Chromatin immunoprecipitation (ChIP), ChIP-loop assay, quantitative RT-PCR in Mecp2-null mice Nature genetics High 15608638
2009 MeCP2 controls an epigenetic relay pathway promoting myofibroblast transdifferentiation and liver fibrosis: MeCP2 is recruited to the PPARgamma promoter where it promotes H3K9 methylation and HP1alpha recruitment, and stimulates EZH2 expression and H3K27 methylation; this pathway is regulated by miR132 translational control of MeCP2. ChIP assay, Mecp2-/y knockout mice in CCl4 fibrosis model, pharmacological inhibition (DZNep), miR132 transfection, qPCR, immunoblotting Gastroenterology High 19843474
2010 MeCP2 represses L1 retrotransposon transcription and retrotransposition in neurons: in the absence of MeCP2, L1 neuronal transcription and retrotransposition are increased in rodents; human RTT patient neurons (derived from iPSCs) with MeCP2 mutations show increased L1 retrotransposition susceptibility. L1 retrotransposition reporter assay in neuronal progenitor cells from Mecp2-null mice and RTT patient iPSC-derived neurons, quantitative PCR Nature High 21085180
2011 MeCP2 function is required in adult neurons: inducible deletion of Mecp2 in adult mice recapitulates the germline knockout RTT-like phenotype, and the beneficial effects of early MeCP2 function are lost soon after deletion, demonstrating an ongoing, non-developmental maintenance role for MeCP2 in adult neurological function. Inducible Cre-lox conditional knockout in adult mice, behavioral phenotyping Science High 21636743
2012 MeCP2 mediates activity-dependent synaptic scaling: bicuculline-induced neuronal activity increases MeCP2 levels, which binds the GluR2 (AMPA receptor subunit) promoter together with HDAC1 and mSin3A, leading to decreased GluR2 expression and reduced mEPSC amplitude; MeCP2 knockdown or genetic deletion blocks this synaptic scaling. shRNA knockdown, Mecp2 genetic deletion, ChIP, mEPSC electrophysiology in rat hippocampal cultures The Journal of neuroscience High 22262897
2012 MeCP2 binds 5-hydroxymethylcytosine (5hmC)-containing DNA with affinity similar to 5mC in brain; MeCP2 is the major 5hmC-binding protein in the brain; the RTT-causing mutation R133C preferentially impairs 5hmC binding, suggesting 5hmC/MeCP2 constitutes a cell-type-specific epigenetic regulatory mechanism. Genome-wide 5hmC/5mC mapping (bisulfite and DIP-seq), affinity binding assays, analysis of R133C mutant MeCP2 binding Cell High 23260135
2013 Intragenic DNA methylation recruits MeCP2 to included alternatively spliced exons to promote exon recognition; MeCP2-enriched exons show local histone hypoacetylation via HDAC recruitment; MeCP2 knockdown causes exon-skipping events overlapping with HDAC inhibitor-induced skipping. ChIP-seq for MeCP2 and histone marks, bisulfite sequencing, MeCP2 knockdown RNA-seq, HDAC inhibitor treatment Cell research High 23938295
2013 SUMOylation of MeCP2 at lysine 223 is necessary for its transcriptional repression function and hippocampal synapse development; SUMOylated MeCP2 recruits HDAC1/2 complexes; K223R mutation abolishes gene repression in neurons and causes synaptic developmental deficits in vitro and in vivo. SUMOylation assay, K223R mutagenesis, co-immunoprecipitation of HDAC complexes, in utero electroporation/in vivo synapse analysis Journal of neurochemistry Medium 24188180
2013 MeCP2 and MBD2 form direct homo- and hetero-interactions in the absence of DNA; the region of MeCP2 comprising amino acids 163–309 is responsible for MeCP2-MBD2 association; these interactions occur in mammalian cells and may contribute to chromatin crosslinking and heterochromatin clustering. In vitro pulldown with purified recombinant proteins, co-immunoprecipitation, fluorescent two-hybrid assay in single cells, deletion mapping PloS one Medium 23335972
2014 MeCP2 SUMOylation (at K412) is induced by NMDA, IGF-1, and CRF; SUMOylation is facilitated by phosphorylation at Ser-421 and Thr-308 and is mediated by the E3 ligase PIAS1; SUMOylated MeCP2 releases CREB from the repressor complex and enhances Bdnf mRNA expression; RTT patient mutations show decreased MeCP2 SUMOylation. SUMOylation assay, PIAS1 E3 ligase identification, phosphorylation-site mutagenesis, co-immunoprecipitation, Bdnf mRNA measurement, behavioral testing in Mecp2 conditional KO mice with rescue Nature communications High 26842955
2014 MeCP2 enforces Foxp3 expression in regulatory T cells during inflammation: in response to inflammatory stimuli, MeCP2 is recruited to the Conserved Non-Coding Sequence 2 (CNS2) region of the Foxp3 locus, where it collaborates with CREB1 to promote local histone H3 acetylation, counteracting inflammation-induced silencing; Treg-specific MeCP2 deletion causes immune dysregulation. ChIP, Treg-specific conditional Mecp2 knockout mice, co-immunoprecipitation with CREB1, histone acetylation assays, colitis model Proceedings of the National Academy of Sciences of the United States of America High 24958888
2014 MeCP2 phosphorylation at Ser421 functions to limit psychostimulant-induced plasticity: MeCP2 Ser421Ala knock-in mice show reduced threshold for locomotor sensitization and enhanced cocaine reinforcement, accompanied by changes in nucleus accumbens medium spiny neuron excitability and gene expression, demonstrating that this phosphorylation event negatively regulates addiction-related circuit plasticity. Ser421Ala knock-in mouse model, behavioral tests (locomotor sensitization, cocaine self-administration), electrophysiology, gene expression analysis The Journal of neuroscience High 24671997
2015 MeCP2 preferentially represses long genes by binding methylated CA (non-CG) sites within them; loss of MeCP2 causes genome-wide length-dependent increases in gene expression in mouse models and human RTT brains; reducing long gene expression attenuates RTT-associated cellular deficits. RNA-seq in Mecp2 mutant mice and human RTT brain, MeCP2 ChIP-seq, rescue by suppression of long genes Nature High 25762136
2017 MeCP2's primary function is to physically connect methylated DNA with the NCoR/SMRT co-repressor complex: mice expressing a minimal MeCP2 retaining only the MBD and NCoR/SMRT interaction domain (approximately half the protein) are near-normal, and a further truncated version lacking the central domain survives >1 year with mild symptoms; this minimal protein reverses neurological symptoms in MeCP2-deficient mice by genetic or viral delivery. Domain-deletion knock-in mouse models, behavioral phenotyping, AAV-mediated brain delivery of truncated MeCP2, genetic reactivation Nature High 29019980
2017 Reduced MeCP2 occupancy near splice junctions facilitates intron retention via decreased recruitment of splicing factor Tra2b and increased RNA polymerase II stalling; MeCP2 depletion in tissues and cells enhances intron retention genome-wide, linking DNA methylation, MeCP2, and co-transcriptional splicing. MeCP2 interactome by mass spectrometry, RNA co-precipitation, MeCP2 ChIP-seq, RNA-seq of MeCP2-depleted tissues Nature communications High 28480880
2017 MeCP2 nuclear localization does not depend on its canonical nuclear localization signal (NLS) but instead requires an intact methyl-CpG binding domain (MBD), suggesting DNA affinity drives nuclear retention; NLS-inactivating mutations do not affect disease progression in a RTT mouse model. Domain-deletion and point-mutation analysis in mouse, NLS-inactivating knock-in mouse model, immunofluorescence localization Cell reports High 30157418
2017 NMR and ITC analyses reveal that MeCP2 MBD binds methylated CpA (mCA) in a strand-specific, orientation-dependent manner with high affinity, distinct from MBD2 which lacks this specificity; RTT-associated missense mutations (T158M, R106W, P101S) destabilize the MBD and equally disrupt mCG and mCA recognition; hydroxymethylation of mCA does not alter binding, whereas hemi-hydroxylation of mCG decreases affinity. Isothermal titration calorimetry (ITC), NMR spectroscopy, disease-mutation analysis Journal of molecular biology High 28450074
2018 MeCP2 directly interacts with and inhibits DNMT3A activity in vitro: MeCP2's transcriptional repression domain (TRD) interacts with the ADD domain of DNMT3A, stabilizing its autoinhibitory conformation and reducing DNA methyltransferase activity; this inhibition is relieved by unmodified H3 tail binding to DNMT3A-ADD; MeCP2 overexpression causes global reduction in DNA methylation in human cells. In vitro DNMT3A methyltransferase activity assay, co-immunoprecipitation, conformationally locked DNMT3A variants, global methylation measurement by mass spectrometry in cells Nucleic acids research High 30102379
2018 Overexpression toxicity in MECP2 duplication syndrome is driven by excessive NCoR1/2 co-repressor recruitment but is independent of HDAC3 catalytic activity: a single amino acid substitution preventing TBL1X(R1) binding (NCoR interaction) is non-toxic at 4× expression; mutations abolishing DNA binding remain toxic; NCoR1/NCoR2 mutations that abolish HDAC3 activation do not rescue toxicity. Mapt locus knock-in mouse models expressing wild-type or mutant MeCP2 at 4× levels, NCoR1/2 HDAC-activation-dead knock-in mice, survival and behavioral phenotyping Genes & development High 30463906
2018 Importin α5 (KPNA1) regulates MeCP2 nuclear localization in hippocampal neurons: knockout of importin α5 reduces MeCP2 nuclear localization and alters expression of MeCP2-regulated genes including sphingosine kinase 1 (Sphk1), linking importin α5-dependent nuclear import to anxiety-related behavior. Importin α5 knockout mouse, immunofluorescence of MeCP2 nuclear localization, behavioral testing, re-expression rescue in ventral hippocampus Cell reports Medium 30540948
2019 MeCP2 represses enhancers through chromosome topology-associated non-CG DNA methylation: genes repressed by MeCP2 are located in megabase-scale topologically associating domains (TADs) enriched for non-CG methylation; MeCP2 represses enhancers within these domains, with strongest repression for enhancers within MeCP2-repressed genes. MeCP2 ChIP-seq, RNA-seq in Mecp2-null neurons, Hi-C/TAD analysis, enhancer activity assays Molecular cell High 31784360
2019 MeCP2 interacts with TCF20 complex at the chromatin interface; RTT-causing mutations in MECP2 disrupt the MeCP2-TCF20 interaction; MeCP2 and TCF20 co-regulate key neuronal genes; reducing Tcf20 partially rescues behavioral deficits in a MECP2 overexpression mouse model, demonstrating functional epistasis. Proximity-dependent biotinylation (BioID) interactome, co-immunoprecipitation, RTT mutation mapping, Tcf20 knockdown rescue in MECP2 duplication mouse model Proceedings of the National Academy of Sciences of the United States of America High 35074918
2019 Phosphorylation of MECP2 at serine 80 (S80) is required for hepatic stellate cell (HSC) proliferation and liver fibrosis: MECP2S80A knock-in mice show reduced HSC proliferation and attenuated fibrosis; MECP2 regulates DNA replication and Fanconi anemia pathway genes in HSCs. MECP2S80A knock-in mouse, CCl4-induced fibrosis model, mRNA/lncRNA array, pathway analysis, HSC proliferation assays Gastroenterology Medium 31352003
2020 MeCP2 is a dynamic component of heterochromatin liquid-like condensates in cells; MeCP2 is stimulated by DNA to form liquid-like condensates in vitro; RTT-causing mutations disrupt condensate formation; MeCP2 condensates selectively incorporate heterochromatin cofactors rather than euchromatic transcription factors, suggesting MeCP2 enhances heterochromatin/euchromatin separation. Live-cell fluorescence imaging, FRAP, in vitro condensate droplet assay with purified protein, RTT mutation analysis, co-partitioning assays with cofactors Nature High 32698189
2021 MeCP2 recognition of non-CG methylation (specifically mCAC) is an essential target for normal brain function: knock-in mice expressing a domain-swap MBD (from MBD2) that can only bind mCG—not mCAC—display severe Rett-syndrome-like phenotypes, demonstrating that MeCP2 interaction with mCAC is required for neurological function and explains the delayed postnatal onset of RTT (coinciding with mCAC accumulation). MBD domain-swap knock-in mice, behavioral phenotyping, transcriptomic analysis in null and domain-swap mice Molecular cell High 33561390
2021 MeCP2 is a microsatellite binding protein that specifically recognizes hydroxymethylated CA repeats; depletion of MeCP2 causes nucleosome accumulation on CA repeats and genome-wide transcriptional dysregulation; structural analysis reveals that Arg133 specifically recognizes the 5hmC-modified CA strand, and R133C RTT mutation disrupts this interaction. Crystal/cryo structure of MeCP2 MBD with hydroxymethylated CA repeat DNA, biochemical binding assays, MeCP2 depletion with ChIP-seq and RNA-seq, R133C mutation analysis Science High 34324427
2024 MECP2 directly interacts with RNA Polymerase II and acts as a positive co-factor for transcription at CpG-rich promoter-proximal regions in human neurons: MECP2 occupies promoter-proximal regions of >4,000 genes together with RNA Pol II; genes co-occupied by MECP2 and RNA Pol II show reduced expression in neurons with RTT-causing MECP2 mutations, indicating MECP2 promotes rather than represses expression at these loci. CUT&Tag for MECP2 and RNA Pol II in human neurons, transcriptome analysis, proteome analysis, co-immunoprecipitation of MECP2 and RNA Pol II, MECP2 patient mutation analysis Neuron High 38697112

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nature genetics 3766 10508514
1998 Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature 2676 9620804
1998 Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription. Nature genetics 2128 9620779
2013 Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature 1778 24390342
2012 Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. Cell 1718 22658674
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2004 Large-scale characterization of HeLa cell nuclear phosphoproteins. Proceedings of the National Academy of Sciences of the United States of America 1159 15302935
2003 DNA methylation-related chromatin remodeling in activity-dependent BDNF gene regulation. Science (New York, N.Y.) 1120 14593184
1992 Purification, sequence, and cellular localization of a novel chromosomal protein that binds to methylated DNA. Cell 1120 1606614
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
1997 MeCP2 is a transcriptional repressor with abundant binding sites in genomic chromatin. Cell 1055 9038338
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2005 The DNA sequence of the human X chromosome. Nature 816 15772651
2000 DNA cloning using in vitro site-specific recombination. Genome research 815 11076863
2002 The methyl-CpG-binding protein MeCP2 links DNA methylation to histone methylation. The Journal of biological chemistry 757 12427740
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2012 MeCP2 binds to 5hmC enriched within active genes and accessible chromatin in the nervous system. Cell 742 23260135
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2005 Duplication of the MECP2 region is a frequent cause of severe mental retardation and progressive neurological symptoms in males. American journal of human genetics 495 16080119
2004 Mild overexpression of MeCP2 causes a progressive neurological disorder in mice. Human molecular genetics 494 15351775
2010 L1 retrotransposition in neurons is modulated by MeCP2. Nature 479 21085180
2015 Disruption of DNA-methylation-dependent long gene repression in Rett syndrome. Nature 460 25762136
2013 Intragenic DNA methylation modulates alternative splicing by recruiting MeCP2 to promote exon recognition. Cell research 440 23938295
2004 Loss of silent-chromatin looping and impaired imprinting of DLX5 in Rett syndrome. Nature genetics 439 15608638
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
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