Affinage

MBD2

Methyl-CpG-binding domain protein 2 · UniProt Q9UBB5

Length
411 aa
Mass
43.3 kDa
Annotated
2026-06-10
100 papers in source corpus 35 papers cited in narrative 35 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MBD2 is the methylated-DNA-recognition subunit of the MeCP1/NuRD repressor complex, linking symmetric mCpG methylation to transcriptional silencing through histone deacetylation and nucleosome remodeling (PMID:10471499, PMID:11274056, PMID:16778143). Its methyl-binding domain engages a methylated CpG in a single orientation whose affinity is tuned by the guanine immediately following the mCpG, with DNA binding stabilizing the central β-sheet of the domain (PMID:21531701). MBD2 nucleates the NuRD machinery through two distinct contacts: an anti-parallel coiled-coil interaction with GATAD2A/p66α that recruits the CHD4/Mi-2β remodeling ATPase, and an intrinsically disordered region requiring residues Arg286/Leu287 that engages the HDAC core (RbAp48, HDAC2, MTA2); mutating either domain dissociates the respective module and abolishes silencing of methylated targets such as γ-globin and PRSS8 (PMID:21490301, PMID:25753662, PMID:23239876, PMID:31004025). Through this complex MBD2 silences methylated loci including the ρ-globin gene, p14/ARF and p16/INK4A, and the inactive-X Xist locus, where its action is non-redundant with other MBD proteins (PMID:16778143, PMID:11309512, PMID:17353271). MBD2 repressive output is regulated post-translationally and by splicing: PRMT5-mediated arginine methylation of its RG-rich N-terminus inhibits DNA and HDAC-complex binding, while alternative splicing generates MBD2a and MBD2c isoforms with opposing transcriptional and cell-fate activities (PMID:16428440, PMID:16980624, PMID:24813856, PMID:33402389). Beyond repression, MBD2 associates with DNMT1/DNMT3A to maintain cancer-specific de novo methylation and, in defined contexts such as the Foxp3 TSDR, facilitates Tet2-dependent demethylation and gene activation (PMID:27593931, PMID:23979593).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1999 High

    Established MBD2 as an HDAC-dependent transcriptional repressor rather than a demethylase, defining its mode of action at methylated DNA.

    Evidence Co-IP of endogenous MBD2 with HDAC1, affinity purification of the corepressor complex, and TSA-sensitive reporter assays in HeLa cells

    PMID:10471499

    Open questions at the time
    • Did not define which DNA-binding subunit role MBD2 plays in MeCP1
    • No genetic loss-of-function evidence
  2. 2000 Medium

    Showed MBD2 dimerizes with MBD3 and co-localizes with DNMT1 at replication foci, linking methyl-CpG recognition to the methylation maintenance machinery.

    Evidence In vitro binding, co-IP, and replication-foci immunofluorescence

    PMID:10947852

    Open questions at the time
    • Functional consequence of DNMT1 association undefined
    • Hemi-methylated DNA binding by the heterodimer not validated in vivo
  3. 2001 High

    Genetic knockout placed MBD2 as the methylated-DNA-binding subunit recruiting the MeCP1 complex, distinct from MBD3's role in NuRD.

    Evidence Mbd2-/- mice, methylated-template reporter assays, and biochemical fractionation

    PMID:11274056

    Open questions at the time
    • Mild phenotype leaves physiological targets open
    • Did not resolve domain requirements for complex recruitment
  4. 2001 Medium

    Demonstrated MBD2 occupies methylated tumor-suppressor CpG islands and cooperates with HDACs and DNA methylation to silence them.

    Evidence ChIP at p14/ARF and p16/INK4A and synergistic reactivation by 5-aza-dC plus TSA in colon cancer cells; recruitment by the zinc-finger protein MIZF

    PMID:11309512 PMID:11553631

    Open questions at the time
    • Direct vs indirect promoter occupancy not separated
    • Locus selectivity mechanism unresolved
  5. 2006 High

    Identified PRMT5-mediated arginine methylation of MBD2 as a negative regulator of its DNA- and HDAC-binding and repressive function.

    Evidence MS interactome, in vitro methylation, EMSA, co-IP, ChIP, and reporter assays

    PMID:16428440 PMID:16980624

    Open questions at the time
    • Stoichiometry and dynamics of methylation in vivo unknown
    • Whether methylation is reversed by a demethylase not addressed
  6. 2006 High

    Defined p66α/p66β as bridging MBD2 to histones within NuRD and showed histone-tail acetylation antagonizes this binding, coupling acetylation state to complex assembly.

    Evidence Yeast two-hybrid, mutagenesis, co-IP, RNAi, in vitro histone-tail binding, and complex purification from primary erythroid cells

    PMID:12183469 PMID:16415179 PMID:16778143

    Open questions at the time
    • Structural basis of the MBD2-p66 contact not yet resolved
    • How acetylation displaces p66 mechanistically unclear
  7. 2011 High

    Provided structural definition of MBD2's two recruitment modules: the coiled-coil that brings in CHD4 and the methyl-DNA-binding domain that reads the mCpG with orientation specificity.

    Evidence Solution NMR of the coiled-coil and of the MBD-DNA complex, plus dominant-negative peptide rescue of globin silencing

    PMID:21490301 PMID:21531701

    Open questions at the time
    • HDAC-core recruitment determinants not yet mapped at this stage
    • In vivo relevance of flanking-sequence preference beyond globin
  8. 2012 High

    Characterized the MBD2-GATAD2A interaction as a high-affinity anti-parallel heterodimeric coiled-coil and showed MBD2/methyl-DNA is required for CHD4 chromatin recruitment.

    Evidence Analytical ultracentrifugation, CD, mutagenesis; ChIP and siRNA at the mb-1/Cd79a promoter

    PMID:23071088 PMID:23239876

    Open questions at the time
    • Affinity hierarchy among MBD paralogs not linked to in vivo complex choice
    • CHD4 catalytic contribution at endogenous loci partially defined
  9. 2015 High

    Mapped the HDAC-core recruitment to an intrinsically disordered region requiring Arg286/Leu287, completing the two-module model of MBD2-NuRD assembly.

    Evidence IDR biophysics, mutagenesis, co-IP, ChIP, and reporter assays at PRSS8 in breast cancer cells

    PMID:25753662

    Open questions at the time
    • Structure of the IDR-HDAC core contact unresolved
    • Whether IDR phosphorylation/modification regulates this contact unknown
  10. 2019 High

    Functionally separated the coiled-coil (CHD4) and IDR (HDAC core) recruitment activities in primary human erythroid cells, validating each as required for γ-globin silencing.

    Evidence CRISPR KO, shRNA, domain-mutant rescue, and co-IP in adult erythroid progenitors

    PMID:31004025

    Open questions at the time
    • Therapeutic targeting feasibility not established
    • Genome-wide consequences of disruption not profiled
  11. 2013 High

    Revealed a non-repressive, activating role for MBD2 by showing it facilitates Tet2-dependent demethylation of the Foxp3 TSDR to sustain Treg function.

    Evidence Mbd2-/-, ChIP for Mbd2 and Tet2, bisulfite sequencing, and Treg suppression assays in vitro and in vivo

    PMID:23979593

    Open questions at the time
    • How MBD2 promotes Tet2 recruitment mechanistically unclear
    • Reconciliation with its repressive NuRD role at other loci
  12. 2016 Medium

    Showed MBD2 participates in writing and propagating cancer-specific de novo methylation through association with DNMT1/DNMT3A.

    Evidence siRNA and Mbd2-/- cells, methylated-construct assays, bisulfite pyrosequencing, genome-wide profiling, and co-IP at GSTP1

    PMID:27593931

    Open questions at the time
    • Whether DNMT recruitment is direct vs complex-mediated
    • Generality across the cancer methylome not established
  13. 2014 Medium

    Established that alternative splicing generates functionally opposing MBD2 isoforms controlling differentiation versus pluripotency.

    Evidence SFRS2 manipulation, isoform overexpression, co-IP with NuRD, ChIP at OCT4/NANOG, and reprogramming assays

    PMID:23255147 PMID:24813856

    Open questions at the time
    • Structural basis for isoform-specific NuRD interaction unclear
    • Single-lab isoform functional assignments
  14. 2021 Medium

    Extended isoform biology to disease, showing hypoxia/HIF1α-driven SRSF2 splicing favors MBD2a to activate FZD1 and drive breast cancer metastasis.

    Evidence Splicing analysis, HIF1/SRSF2 manipulation, ChIP at FZD1, and metastasis assays with patient correlation

    PMID:33402389

    Open questions at the time
    • Mechanism of MBD2a-mediated activation vs repression at FZD1 unresolved
    • Competition model between isoforms not structurally defined
  15. 2023 Medium

    Demonstrated that MBD2a's methyl-DNA binding and GR-rich repeat restrict its NuRD functions relative to MBD3 during ESC differentiation.

    Evidence MBD3 KO ESCs rescued by domain-swapped and isoform MBD2 variants

    PMID:37385984

    Open questions at the time
    • How these domains limit NuRD activity mechanistically unclear
    • Endogenous regulation of isoform choice in ESCs undefined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How MBD2 switches between NuRD-mediated repression and context-specific facilitation of active demethylation/activation at the same molecular machinery remains unresolved.
  • No unifying mechanism distinguishing repressive vs activating MBD2 occupancy
  • Structural basis of MBD2-DNMT and MBD2-Tet2 functional coupling unknown
  • Determinants of locus- and isoform-specific outcome not defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 5 GO:0140110 transcription regulator activity 5 GO:0060090 molecular adaptor activity 4
Localization
GO:0005634 nucleus 4 GO:0000228 nuclear chromosome 3
Pathway
R-HSA-1643685 Disease 4 R-HSA-4839726 Chromatin organization 4 R-HSA-74160 Gene expression (Transcription) 4
Partners
CHD4DNMT1GATAD2AHDAC2MBD3MTA2PRMT5RBBP4
Complex memberships
MeCP1NuRD

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 MBD2 is a transcriptional repressor that associates with histone deacetylase (HDAC1) in the MeCP1 repressor complex in HeLa cells; exogenous MBD2 represses transcription in a transient assay, and repression is relieved by the HDAC inhibitor trichostatin A. MBD2 was found NOT to demethylate DNA in these experiments. Antibody-based co-immunoprecipitation of endogenous MBD2 with HDAC1; affinity purification of HDAC1 corepressor complex; transient transcription reporter assay with TSA treatment Nature genetics High 10471499
2001 MBD2 is a component of the MeCP1 complex; Mbd2-/- mice are viable and fertile but lack MeCP1 activity and fail to fully silence exogenous methylated templates, establishing MBD2 as the methylated-DNA-binding subunit that recruits the MeCP1 repressor complex. MBD3 (not MBD2) is the essential component of the Mi-2/NuRD complex. Gene targeting (knockout mice); transient methylated reporter assay in Mbd2-/- cells; biochemical fractionation Genes & development High 11274056
2000 MBD2 and MBD3 form homo- and hetero-dimers in vitro and in vivo; the MBD2-MBD3 heterodimer binds hemi-methylated DNA (not previously reported for any MBD family member). MBD2 and MBD3 co-localize with DNMT1 at replication foci in late S phase, and DNMT1 co-immunoprecipitates with MBD2 and MBD3. In vitro binding assays; co-immunoprecipitation; immunofluorescence co-localization at replication foci Genes to cells Medium 10947852
2006 MBD2 and MBD3 assemble into mutually exclusive NuRD-like complexes (MBD2/NuRD and MBD3/NuRD). PRMT5 and its cofactor MEP50 are specific MBD2/NuRD interactors; PRMT5 stably associates with and methylates the RG-rich N-terminus of MBD2. ChIP showed MBD2 and PRMT5 are co-recruited to CpG islands in a methylation-dependent manner, with H4R3 methylated at these loci. Protein tagging and mass spectrometry; co-immunoprecipitation; in vitro methylation assay; chromatin immunoprecipitation (ChIP) Molecular and cellular biology High 16428440
2006 Arginine methylation of MBD2 by protein arginine methyltransferases (PRMTs) inhibits MBD2 function: arginine methylation reduces MBD2-methylated DNA complex formation, reduces MBD2-HDAC repression complex formation, and impairs transcriptional repression by MBD2 in cells. In vitro methylation assays; electrophoretic mobility shift assay (EMSA); co-immunoprecipitation; transcriptional reporter assay Molecular and cellular biology High 16980624
2002 Two highly related p66 proteins (hp66α and hp66β) directly interact with MBD2 and MBD3 as subunits of the MeCP1/NuRD complex; hp66α is a potent transcriptional repressor (~100-fold repression) and co-localizes with MBD2 in a speckled nuclear pattern. hp66α interacts via two interaction domains whereas hp66β uses a single domain. Yeast two-hybrid screen; co-precipitation in vivo; confocal microscopy; transcriptional reporter assay The Journal of biological chemistry Medium 12183469
2006 p66α and p66β mediate interaction between MBD2 and histones within the Mi-2/NuRD complex; a single amino acid mutation in p66α abolishes in vivo binding to MBD2 and impairs MBD2-mediated repression; both p66 proteins interact with tails of all octamer histones in vitro, and acetylation of histone tails interferes with p66 binding; subnuclear distribution of p66α and p66β depends on MBD2. Mutagenesis; co-immunoprecipitation; RNA interference knockdown; in vitro histone tail binding assay; confocal microscopy Nucleic acids research High 16415179
2011 The coiled-coil interaction between MBD2 and p66α recruits Mi-2 (CHD4) to the MBD2-NuRD complex and is required for MBD2-dependent DNA methylation-driven globin gene silencing; enforced expression of the isolated p66α coiled-coil domain relieves MBD2-mediated globin gene silencing in vivo. NMR/solution structure of coiled-coil; biophysical binding assays; dominant-negative peptide expression; gene expression assays in erythroid cells Proceedings of the National Academy of Sciences of the United States of America High 21490301
2011 Solution NMR structure of chicken MBD2 methyl-binding domain bound to a methylated DNA sequence from the ρ-globin promoter revealed that MBD2 binds in a single orientation on the target sequence; binding orientation and affinity depend on the guanine immediately following the mCpG dinucleotide; DNA binding stabilizes the central β-sheet of MBD2. Solution NMR structure determination; dynamic analysis; biophysical binding assays Nucleic acids research High 21531701
2015 An intrinsically disordered region (IDR) of MBD2 (MBD2IDR) recruits the histone deacetylase core components of NuRD (RbAp48, HDAC2, MTA2) through a critical contact requiring residues Arg286 and Leu287; mutating these residues abrogates MBD2-HDAC core interaction and impairs MBD2-mediated repression of methylated PRSS8 tumor suppressor gene in breast cancer cells. The IDR also increases overall MBD2 binding affinity for methylated DNA. Biophysical analyses (IDR characterization); mutagenesis; co-immunoprecipitation; transcriptional reporter assay; ChIP Nucleic acids research High 25753662
2012 Unique anti-parallel heterodimeric coiled-coil interaction between MBD2 and GATAD2A/p66α: the individual peptides remain monomeric in isolation; complementary electrostatic surface potentials and inherent helical content drive high-affinity heterodimeric specificity. Binding affinity hierarchy for p66α is MBD2 ≈ MBD3 > MBD3L1 ≈ MBD3L2. Analytical ultracentrifugation; circular dichroism; biophysical binding analyses; mutagenesis of coiled-coil domains The Journal of biological chemistry High 23239876
2019 Disruption of MBD2-NuRD complex (but not MBD3-NuRD) in human adult erythroid cells causes 10-20-fold increase in γ-globin expression; MBD2 exerts repressive effects through CHD4 recruitment via the coiled-coil domain and HDAC core recruitment via the IDR; coiled-coil and IDR mutant MBD2 proteins fail to silence γ-globin and dissociate CHD4 and HDAC core complex components, respectively, as shown by co-immunoprecipitation. CRISPR-Cas9 knockout in erythroid progenitor cells; shRNA knockdown in primary adult erythroid cells; rescue with wild-type and domain mutant MBD2; co-immunoprecipitation; RT-PCR; HPLC Haematologica High 31004025
2012 MBD2 and methylated DNA are required for association of CHD4 with target gene (mb-1/Cd79a) promoter chromatin; loss of MBD2 expression or DNA methylation impairs CHD4 chromatin association and enhances transcription of the B cell-specific mb-1 gene; NuRD repressive function requires both the chromodomains and ATPase/helicase domain of CHD4. Chromatin immunoprecipitation (ChIP); siRNA knockdown of MBD2; transcriptional reporter assay; domain mutant analysis of CHD4 Molecular and cellular biology Medium 23071088
2006 MBD2 is a critical component of a MeCP1-like complex purified from primary chicken erythroid cells, co-eluting with MBD2, RBAP48, HDAC2, MTA1, p66, and Mi-2; ChIP shows MBD2 enrichment at the methylated, transcriptionally silent ρ-globin gene but not the active βA-globin gene; knockdown of MBD2 upregulates a methylated ρ-gene construct in MEL cells. Chromatographic purification of complex from primary erythroid cells; mass spectrometry identification; gel-filtration analysis; pull-down assays; ChIP; siRNA knockdown Blood High 16778143
2001 MBD2 is physically associated (by ChIP) with the methylated p14/ARF and p16/INK4A promoter CpG islands in human neoplastic colon cell lines, and is associated with exclusion of acetylated histones H3 and H4 from these regions. Treatment with TSA and 5-aza-dC synergistically reactivates these genes, implying cooperativity between MBD2-recruited HDACs and DNA methylation. Chromatin immunoprecipitation (ChIP); chemical treatment (5-aza-dC, TSA); quantitative RT-PCR Proceedings of the National Academy of Sciences of the United States of America Medium 11309512
2008 Mbd2 deficiency partially suppresses the Wnt signaling pathway activated by Apc loss in the mouse intestine. Mechanistically, Mbd2 deficiency elevates levels of Lect2 (a Wnt pathway repressor) and Mbd2 binds the Lect2 promoter in association with NuRD, thereby suppressing Lect2 expression and sustaining Wnt signaling. Genetic epistasis (Mbd2-/- crossed to Apc conditional knockout); microarray expression analysis; ChIP (Mbd2 at Lect2 promoter); Lect2 overexpression functional assay Molecular and cellular biology Medium 18644872
2009 Focal adhesion kinase (FAK) interacts with MBD2 in vitro, in myotubes, and in isolated muscle fibres; the interaction is increased by oxidative stress and enhances FAK nuclear localization. Nuclear FAK-MBD2 complexes alter heterochromatin reorganization, decrease MBD2 association with HDAC1 and the methylated myogenin promoter CpG site, thereby inducing myogenin expression and muscle terminal differentiation. Co-immunoprecipitation; in vitro binding assay; immunofluorescence; dominant-negative MBD2 expression; FAK miRNA knockdown; myogenin promoter ChIP The EMBO journal Medium 19661918
2001 MIZF (a novel zinc finger protein) interacts directly with MBD2 via four of its seven C-terminal zinc fingers; this interaction is required for MIZF-dependent transcriptional repression that is sensitive to TSA, implicating recruitment of HDAC-containing complexes via MBD2. MIZF co-localizes with MBD2 in some nuclear areas. Yeast two-hybrid screen; in vitro binding assay; co-immunoprecipitation; transcriptional reporter assay; confocal immunofluorescence The Journal of biological chemistry Medium 11553631
2004 MBD3L1 interacts with MBD2 (but not MBD3) in vitro and in yeast two-hybrid assays, co-localizes with MBD2 at pericentromeric heterochromatin in vivo, and enhances MBD2-dependent transcriptional repression of methylated DNA. GST pull-down shows MBD3L1 associates with NuRD components HDAC1, HDAC2, MTA2, RbAp46, and RbAp48 through MBD2. Yeast two-hybrid; GST pull-down; gel shift (EMSA) supershift; co-immunoprecipitation; confocal microscopy; transcriptional reporter assay The Journal of biological chemistry Medium 15456747
2003 MBDin (a novel GTP-binding protein) interacts with MBD2 via the C-terminal 46-amino-acid region of MBD2; MBDin relieves MBD2-mediated transcriptional repression from methylated promoters without inducing DNA demethylation. MBDin is cytoplasmic but accumulates in the nucleus and co-localizes with MBD2 at heavily methylated satellite DNA when its NES is disrupted. Yeast two-hybrid; co-immunoprecipitation; fluorescence microscopy; transcriptional reporter assay; bisulfite sequencing (negative: no demethylation) Molecular and cellular biology Medium 12588985
2006 TACC3 interacts with MBD2 and forms a mutually exclusive complex with pCAF (histone acetyltransferase) that is incompatible with the MBD2-HDAC2 repressor complex; TACC3 overexpression increases HAT activity associated with MBD2 in vivo and reactivates methylated promoters without demethylation. Co-immunoprecipitation; HAT enzymatic assay; transcriptional reporter assay Nucleic acids research Medium 16410616
2007 Mbd2 deficiency causes significant low-level reactivation of Xist on the active X chromosome; silencing is restored by exogenous Mbd2. Xist repression in Mbd2-null cells is hypersensitive to TSA and to Dnmt1 depletion, implicating Mbd2 as a mediator of the DNA methylation signal at this locus. Deficiencies of Mbd1, MeCP2, and Kaiso had no detectable effect, showing locus-specific non-redundancy. Gene-targeted knockout cells; RNA expression analysis; TSA treatment; siRNA depletion of Dnmt1; rescue by exogenous Mbd2 expression Molecular and cellular biology Medium 17353271
2013 Mbd2 promotes demethylation of the Foxp3 TSDR (Treg-specific demethylation region) and Treg suppressive function: ChIP shows Mbd2 binds the TSDR in Treg cells; Mbd2 knockout causes >75% methylation at the TSDR and impairs Tet2 binding; reintroduction of Mbd2 into Mbd2-null Treg cells restores TSDR demethylation, Foxp3 expression, and Treg function. Gene targeting (Mbd2-/-); siRNA knockdown; ChIP (Mbd2 and Tet2 at TSDR); bisulfite sequencing; Treg suppression functional assay in vitro and in vivo Molecular and cellular biology High 23979593
2014 SFRS2 (an OCT4 target splicing factor) regulates alternative splicing of MBD2 to produce isoforms with opposing functions: MBD2a preferentially interacts with repressive NuRD factors and promotes differentiation, whereas MBD2c enhances reprogramming to pluripotency. Both isoforms are enriched at OCT4 and NANOG promoters. Global gene expression and proteomic integration; SFRS2 knockdown; MBD2 isoform overexpression; co-immunoprecipitation (MBD2a with NuRD); ChIP at OCT4/NANOG promoters; reprogramming assay Cell stem cell Medium 24813856
2013 MBD2 acts as an epigenetic suppressor blocking full iPSC reprogramming by directly binding to methylated NANOG promoter elements and preventing NANOG transcriptional activation; overexpression of miR-302 cluster suppresses MBD2 expression and thereby increases NANOG expression and complete reprogramming efficiency. ChIP (MBD2 at NANOG promoter); MBD2 overexpression/knockdown; reprogramming efficiency assay; miR-302 overexpression Stem cells (Dayton, Ohio) Medium 23255147
2016 MBD2 depletion results in inhibition of both maintenance and spread of de novo methylation at the GSTP1 promoter CpG island in prostate cancer cells and Mbd2-/- fibroblasts; de novo methylation is rescued by transient Mbd2 re-expression; co-immunoprecipitation shows MBD2 associates with DNMT1 and DNMT3A, indicating MBD2 participates in 'writing' the cancer methylome at specific regulatory regions. Mbd2 siRNA depletion and Mbd2-/- fibroblasts; transfected methylated construct assay; bisulfite pyrosequencing; genome-wide methylation profiling; co-immunoprecipitation (MBD2-DNMT1/3A) Oncogene Medium 27593931
2016 Chromatin localization of Mbd2 and Mbd3 is highly overlapping in ESCs and both proteins are interdependent for chromatin association (each is required for the other's chromatin binding). Both are required for normal levels of cytosine methylation and hydroxymethylation, and regulate overlapping gene sets also regulated by DNA methylation/hydroxymethylation factors. ChIP-seq; conditional knockout ESCs; DNA methylation/hydroxymethylation profiling; gene expression analysis eLife Medium 27849519
2021 MBD2a (full-length isoform) promotes breast cancer metastasis by binding promoter CpG islands to activate FZD1 expression, thereby promoting EMT; MBD2c (short form) suppresses metastasis. Under hypoxia, HIF1α represses SRSF2-mediated alternative splicing, favoring MBD2a production. MBD2a and MBD2c compete for binding at the FZD1 promoter. Alternative splicing analysis; HIF1 pathway manipulation; SRSF2 knockdown/overexpression; ChIP at FZD1 promoter; metastasis assays in vitro and in vivo; patient data correlation Cancer research Medium 33402389
2004 MBD2 selectively binds to the methylated delta-opioid receptor (mDOR) promoter and forms a MeCP1-like protein complex with Sp3; both MBD2 and Sp3 together mediate methylation-dependent transcriptional repression of mDOR in Neuro2A cells. Sp3 levels decrease upon chemical demethylation, and increasing Sp3 promotes repression only when the promoter is methylated. EMSA supershift; co-immunoprecipitation (implicit from complex formation); 5-aza-dC treatment; Sp3 overexpression; transcriptional reporter assay The Journal of biological chemistry Medium 12890683
2008 MBD2 associates with the methylated p14ARF promoter in RKO colon cancer cells by ChIP; stable RNAi-mediated knockdown of MBD2 leads to selective upregulation of p14ARF but not p16INK4A; repression is restored by exogenous mouse MBD2, demonstrating a direct and gene-selective repressive role for MBD2. Stable RNAi knockdown; ChIP; RT-PCR expression analysis; rescue by exogenous MBD2 Pathobiology Medium 18931530
2013 MBD2 binds hypomethylated and hypermethylated gene regions in liver cancer cells; at activated target genes, MBD2 co-localizes with the transcription factor CEBPA, and MBD2 binding at these positions is reduced upon CEBPA depletion. MBD2 depletion changes RNA Pol II binding and DNA methylation state at target genes, indicating MBD2 can function both in activation and repression depending on genomic context. ChIP with microarray (ChIP-chip) for MBD2, RNA Pol II, CEBPA; methylated DNA immunoprecipitation; siRNA knockdown of MBD2 and CEBPA Carcinogenesis Medium 23955541
2021 Mbd2 selectively binds to the Ship promoter in macrophages by ChIP, repressing Ship expression and thereby enhancing PI3K/Akt signaling to promote macrophage M2 polarization and TGF-β1 production. Mbd2 deficiency in macrophages protects mice against bleomycin-induced pulmonary fibrosis. Macrophage-specific Mbd2 knockout; ChIP (Mbd2 at Ship promoter); PI3K/Akt pathway analysis; in vivo bleomycin model; siRNA liposome delivery Science advances Medium 33277324
2020 MBD2 mediates septic AKI through direct binding to CpG islands in the PKCη promoter (as shown by ChIP), inducing PKCη expression via promoter hypomethylation; PKCη then activates p38MAPK and ERK1/2 signaling to promote apoptosis and inflammation. MBD2 knockout or siRNA suppresses this pathway and attenuates AKI. ChIP (MBD2 at PKCη promoter); MBD2 KO and siRNA; PKCη siRNA; global gene expression analysis; in vivo CLP model Molecular therapy. Nucleic acids Medium 33335794
2013 MBD2 directly interacts with MeCP2 (and self-associates) in vitro using purified recombinant proteins and in mammalian cells by co-immunoprecipitation; the region MBD2 amino acids 1–152 and MeCP2 amino acids 163–309 are responsible for this hetero-interaction; both proteins can heterodimerize independently of DNA. In vitro binding assay with recombinant proteins; co-immunoprecipitation; fluorescent two-hybrid assay in single cells; deletion mapping PloS one Medium 23335972
2023 MBD2a (full-length) and MBD2b (lacking GR-rich N-terminal repeat) show distinct functional capacities within NuRD during ESC differentiation: MBD2b fully rescues the Mbd3 KO differentiation block while MBD2a only partially does so; removing MBD2a's methylated DNA binding capacity or GR-rich repeat enables full functional redundancy with MBD3, indicating these domains restrict MBD2a's NuRD functions. CRISPR-based MBD3 KO ESCs; rescue by domain-swapped and isoform MBD2 variants; differentiation assays; domain deletion analysis Nature communications Medium 37385984

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 MBD2 is a transcriptional repressor belonging to the MeCP1 histone deacetylase complex. Nature genetics 720 10471499
2001 Closely related proteins MBD2 and MBD3 play distinctive but interacting roles in mouse development. Genes & development 394 11274056
2006 MBD2/NuRD and MBD3/NuRD, two distinct complexes with different biochemical and functional properties. Molecular and cellular biology 271 16428440
2021 MBD2 serves as a viable target against pulmonary fibrosis by inhibiting macrophage M2 program. Science advances 201 33277324
2001 Selective association of the methyl-CpG binding protein MBD2 with the silent p14/p16 locus in human neoplasia. Proceedings of the National Academy of Sciences of the United States of America 173 11309512
2002 Promoter-specific activation and demethylation by MBD2/demethylase. The Journal of biological chemistry 139 12177048
2003 Deficiency of Mbd2 suppresses intestinal tumorigenesis. Nature genetics 138 12730693
2011 p66Alpha-MBD2 coiled-coil interaction and recruitment of Mi-2 are critical for globin gene silencing by the MBD2-NuRD complex. Proceedings of the National Academy of Sciences of the United States of America 122 21490301
2011 Neonatal exposure to estradiol/bisphenol A alters promoter methylation and expression of Nsbp1 and Hpcal1 genes and transcriptional programs of Dnmt3a/b and Mbd2/4 in the rat prostate gland throughout life. Endocrinology 121 22109888
2000 MBD2-MBD3 complex binds to hemi-methylated DNA and forms a complex containing DNMT1 at the replication foci in late S phase. Genes to cells : devoted to molecular & cellular mechanisms 121 10947852
2014 Alternative splicing of MBD2 supports self-renewal in human pluripotent stem cells. Cell stem cell 93 24813856
2013 Mbd2 promotes foxp3 demethylation and T-regulatory-cell function. Molecular and cellular biology 92 23979593
1999 Genomic structure and chromosomal mapping of the murine and human Mbd1, Mbd2, Mbd3, and Mbd4 genes. Mammalian genome : official journal of the International Mammalian Genome Society 90 10441743
2009 Regulation of heterochromatin remodelling and myogenin expression during muscle differentiation by FAK interaction with MBD2. The EMBO journal 89 19661918
2013 Decreased levels of miR-224 and the passenger strand of miR-221 increase MBD2, suppressing maspin and promoting colorectal tumor growth and metastasis in mice. Gastroenterology 88 23770133
2010 Global DNA methylation, DNMT1, and MBD2 in patients with rheumatoid arthritis. Immunology letters 83 20937307
2011 Solution structure and dynamic analysis of chicken MBD2 methyl binding domain bound to a target-methylated DNA sequence. Nucleic acids research 81 21531701
2002 Two highly related p66 proteins comprise a new family of potent transcriptional repressors interacting with MBD2 and MBD3. The Journal of biological chemistry 81 12183469
2013 Epigenetic regulation of NANOG by miR-302 cluster-MBD2 completes induced pluripotent stem cell reprogramming. Stem cells (Dayton, Ohio) 78 23255147
2007 Homocysteine-mediated expression of SAHH, DNMTs, MBD2, and DNA hypomethylation potential pathogenic mechanism in VSMCs. DNA and cell biology 74 17688412
2016 Emerging Molecular and Biological Functions of MBD2, a Reader of DNA Methylation. Frontiers in genetics 71 27303433
2011 Overexpression of MBD2 in glioblastoma maintains epigenetic silencing and inhibits the antiangiogenic function of the tumor suppressor gene BAI1. Cancer research 71 21724586
2015 An intrinsically disordered region of methyl-CpG binding domain protein 2 (MBD2) recruits the histone deacetylase core of the NuRD complex. Nucleic acids research 69 25753662
2006 p66alpha and p66beta of the Mi-2/NuRD complex mediate MBD2 and histone interaction. Nucleic acids research 67 16415179
2007 Transcript overexpression of the MBD2 and MBD4 genes in CD4+ T cells from systemic lupus erythematosus patients. Journal of leukocyte biology 64 17360956
2015 A dominant role for the methyl-CpG-binding protein Mbd2 in controlling Th2 induction by dendritic cells. Nature communications 61 25908537
2003 MeCP2 and MBD2 expression in human neoplastic and non-neoplastic breast tissue and its association with oestrogen receptor status. British journal of cancer 61 14612906
2017 MBD2 upregulates miR-301a-5p to induce kidney cell apoptosis during vancomycin-induced AKI. Cell death & disease 60 29022913
2006 Control of the DNA methylation system component MBD2 by protein arginine methylation. Molecular and cellular biology 58 16980624
2006 TACC3 mediates the association of MBD2 with histone acetyltransferases and relieves transcriptional repression of methylated promoters. Nucleic acids research 57 16410616
2005 Role of MBD2 in gene regulation and tumorigenesis. Biochemical Society transactions 56 16246164
2016 Methyl-CpG-binding protein MBD2 plays a key role in maintenance and spread of DNA methylation at CpG islands and shores in cancer. Oncogene 55 27593931
2014 MBD2 and MBD3: elusive functions and mechanisms. Frontiers in genetics 55 25538734
2009 The methyl-CpG binding proteins Mecp2, Mbd2 and Kaiso are dispensable for mouse embryogenesis, but play a redundant function in neural differentiation. PloS one 55 19177165
2010 miR-373 negatively regulates methyl-CpG-binding domain protein 2 (MBD2) in hilar cholangiocarcinoma. Digestive diseases and sciences 54 21086164
2004 Sequence-specific transcriptional repression by an MBD2-interacting zinc finger protein MIZF. Nucleic acids research 51 14752047
2014 MBD2 regulates TH17 differentiation and experimental autoimmune encephalomyelitis by controlling the homeostasis of T-bet/Hlx axis. Journal of autoimmunity 50 24934598
2007 Mbd2 contributes to DNA methylation-directed repression of the Xist gene. Molecular and cellular biology 50 17353271
2001 Involvement of a novel zinc finger protein, MIZF, in transcriptional repression by interacting with a methyl-CpG-binding protein, MBD2. The Journal of biological chemistry 50 11553631
2021 Hypoxia-Induced Suppression of Alternative Splicing of MBD2 Promotes Breast Cancer Metastasis via Activation of FZD1. Cancer research 49 33402389
2002 Antisense MBD2 gene therapy inhibits tumorigenesis. The journal of gene medicine 48 12124980
2004 MBD3L1 is a transcriptional repressor that interacts with methyl-CpG-binding protein 2 (MBD2) and components of the NuRD complex. The Journal of biological chemistry 47 15456747
2019 Disruption of the MBD2-NuRD complex but not MBD3-NuRD induces high level HbF expression in human adult erythroid cells. Haematologica 45 31004025
2010 Global DNA methylation, DNMT1, and MBD2 in patients with systemic lupus erythematosus. Lupus 45 21078759
2004 The Drosophila MBD2/3 protein mediates interactions between the MI-2 chromatin complex and CpT/A-methylated DNA. Development (Cambridge, England) 45 15537686
2003 MBDin, a novel MBD2-interacting protein, relieves MBD2 repression potential and reactivates transcription from methylated promoters. Molecular and cellular biology 44 12588985
2016 Loss of Mbd2 Protects Mice Against High-Fat Diet-Induced Obesity and Insulin Resistance by Regulating the Homeostasis of Energy Storage and Expenditure. Diabetes 43 27554473
2014 Genome-wide binding of MBD2 reveals strong preference for highly methylated loci. PloS one 43 24927503
1999 Reduced mRNA expression of the DNA demethylase, MBD2, in human colorectal and stomach cancers. Biochemical and biophysical research communications 43 10544038
2014 The methylated-DNA binding protein MBD2 enhances NGFI-A (egr-1)-mediated transcriptional activation of the glucocorticoid receptor. Philosophical transactions of the Royal Society of London. Series B, Biological sciences 42 25135974
2012 MBD2 and multiple domains of CHD4 are required for transcriptional repression by Mi-2/NuRD complexes. Molecular and cellular biology 42 23071088
2008 Deficiency of Mbd2 attenuates Wnt signaling. Molecular and cellular biology 42 18644872
2002 MeCP2 and MBD2 expression during normal and pathological growth of the human mammary gland. Oncogene 40 11965543
2006 MBD2 is a critical component of a methyl cytosine-binding protein complex isolated from primary erythroid cells. Blood 39 16778143
2002 MBD3L1 and MBD3L2, two new proteins homologous to the methyl-CpG-binding proteins MBD2 and MBD3: characterization of MBD3L1 as a testis-specific transcriptional repressor. Genomics 36 12504854
2019 Increased HERV-E clone 4-1 expression contributes to DNA hypomethylation and IL-17 release from CD4+ T cells via miR-302d/MBD2 in systemic lupus erythematosus. Cell communication and signaling : CCS 35 31412880
2013 Diethylstilbestrol (DES)-stimulated hormonal toxicity is mediated by ERα alteration of target gene methylation patterns and epigenetic modifiers (DNMT3A, MBD2, and HDAC2) in the mouse seminal vesicle. Environmental health perspectives 35 24316720
2004 The Drosophila methyl-DNA binding protein MBD2/3 interacts with the NuRD complex via p55 and MI-2. BMC molecular biology 35 15516265
2020 MBD2 Mediates Septic AKI through Activation of PKCη/p38MAPK and the ERK1/2 Axis. Molecular therapy. Nucleic acids 34 33335794
2013 Direct homo- and hetero-interactions of MeCP2 and MBD2. PloS one 34 23335972
2003 Methyl-CpG-DNA binding proteins in human prostate cancer: expression of CXXC sequence containing MBD1 and repression of MBD2 and MeCP2. Biochemical and biophysical research communications 33 12646234
2021 MBD2 acts as a repressor to maintain the homeostasis of the Th1 program in type 1 diabetes by regulating the STAT1-IFN-γ axis. Cell death and differentiation 32 34420035
2012 Unique features of the anti-parallel, heterodimeric coiled-coil interaction between methyl-cytosine binding domain 2 (MBD2) homologues and GATA zinc finger domain containing 2A (GATAD2A/p66α). The Journal of biological chemistry 32 23239876
2005 MBD3L2 interacts with MBD3 and components of the NuRD complex and can oppose MBD2-MeCP1-mediated methylation silencing. The Journal of biological chemistry 32 15701600
2022 Genetic or siRNA inhibition of MBD2 attenuates the UUO- and I/R-induced renal fibrosis via downregulation of EGR1. Molecular therapy. Nucleic acids 31 35356685
2013 Transcription onset of genes critical in liver carcinogenesis is epigenetically regulated by methylated DNA-binding protein MBD2. Carcinogenesis 31 23955541
2020 Mbd2 Mediates Retinal Cell Apoptosis by Targeting the lncRNA Mbd2-AL1/miR-188-3p/Traf3 Axis in Ischemia/Reperfusion Injury. Molecular therapy. Nucleic acids 30 32074940
2018 MBD2-mediated Th17 differentiation in severe asthma is associated with impaired SOCS3 expression. Experimental cell research 28 30098334
2013 Planarian MBD2/3 is required for adult stem cell pluripotency independently of DNA methylation. Developmental biology 27 24063805
2012 Associations between aberrant DNA methylation and transcript levels of DNMT1 and MBD2 in CD4+T cells from patients with systemic lupus erythematosus. The Australasian journal of dermatology 27 23127209
2010 MBD2 and MeCP2 regulate distinct transitions in the stage-specific differentiation of olfactory receptor neurons. Molecular and cellular neurosciences 27 20188178
2003 MBD1, MBD2 and CGBP genes at chromosome 18q21 are infrequently mutated in human colon and lung cancers. Oncogene 27 12776203
2019 Obesity-induced MBD2_v2 expression promotes tumor-initiating triple-negative breast cancer stem cells. Molecular oncology 26 30636104
2018 MBD2 regulates differentiation and function of Th17 cells in neutrophils- dominant asthma via HIF-1α. Journal of inflammation (London, England) 26 30150897
2010 FAK interaction with MBD2: A link from cell adhesion to nuclear chromatin remodeling? Cell adhesion & migration 26 19949307
2010 Methyl-CpG binding protein MBD2 is implicated in methylation-mediated suppression of miR-373 in hilar cholangiocarcinoma. Oncology reports 26 21165562
2024 MBD2 couples DNA methylation to transposable element silencing during male gametogenesis. Nature plants 25 38225352
2019 Rational discovery of antimetastatic agents targeting the intrinsically disordered region of MBD2. Science advances 25 31799386
2016 DNA methylation directs genomic localization of Mbd2 and Mbd3 in embryonic stem cells. eLife 25 27849519
2013 Association between mRNA levels of DNMT1, DNMT3A, DNMT3B, MBD2 and LINE-1 methylation status in infants with tetralogy of Fallot. International journal of molecular medicine 25 23820632
2017 MBD2 Regulates Th17 Cell Differentiation and Experimental Severe Asthma by Affecting IRF4 Expression. Mediators of inflammation 24 28808358
2014 Alteration of Scn3a expression is mediated via CpG methylation and MBD2 in mouse hippocampus during postnatal development and seizure condition. Biochimica et biophysica acta 22 25459751
2008 MBD2-mediated transcriptional repression of the p14ARF tumor suppressor gene in human colon cancer cells. Pathobiology : journal of immunopathology, molecular and cellular biology 22 18931530
2005 MBD2 deficiency does not accelerate p53 mediated lymphomagenesis. Oncogene 22 15735763
2017 MiR-520b inhibits the development of glioma by directly targeting MBD2. American journal of cancer research 21 28744402
2003 Transcriptional regulation of mouse delta-opioid receptor gene by CpG methylation: involvement of Sp3 and a methyl-CpG-binding protein, MBD2, in transcriptional repression of mouse delta-opioid receptor gene in Neuro2A cells. The Journal of biological chemistry 21 12890683
2021 MBD2 mediates renal cell apoptosis via activation of Tox4 during rhabdomyolysis-induced acute kidney injury. Journal of cellular and molecular medicine 20 33764669
2018 Exogenous IL-6 induces mRNA splice variant MBD2_v2 to promote stemness in TP53 wild-type, African American PCa cells. Molecular oncology 20 29741809
2015 Dynamics of MBD2 deposition across methylated DNA regions during malignant transformation of human mammary epithelial cells. Nucleic acids research 20 26007656
2003 Enhanced antitumor activity of a combination of MBD2-antisense electrotransfer gene therapy and bleomycin electrochemotherapy. The journal of gene medicine 19 14533198
2023 Methyl-CpG binding domain 2 (Mbd2) is an epigenetic regulator of autism-risk genes and cognition. Translational psychiatry 18 37443311
2011 Decreased expression of MBD2 and MBD4 gene and genomic-wide hypomethylation in patients with primary immune thrombocytopenia. Human immunology 18 21377502
2023 Dissecting the roles of MBD2 isoforms and domains in regulating NuRD complex function during cellular differentiation. Nature communications 17 37385984
2018 MBD2 Ablation Impairs Lymphopoiesis and Impedes Progression and Maintenance of T-ALL. Cancer research 17 29330145
2018 Reduced MBD2 expression enhances airway inflammation in bronchial epithelium in COPD. International journal of chronic obstructive pulmonary disease 17 29535511
2018 Deletion of MBD2 inhibits proliferation of chronic myeloid leukaemia blast phase cells. Cancer biology & therapy 17 29565710
2014 Synergistic effects of combined DNA methyltransferase inhibition and MBD2 depletion on breast cancer cells; MBD2 depletion blocks 5-aza-2'-deoxycytidine-triggered invasiveness. Carcinogenesis 17 25178277
2007 Functional diversification of the nematode mbd2/3 gene between Pristionchus pacificus and Caenorhabditis elegans. BMC genetics 17 17725827
2006 RET finger protein enhances MBD2- and MBD4-dependent transcriptional repression. Biochemical and biophysical research communications 17 17049487
2023 miR-146a-3p as a potential novel therapeutic by targeting MBD2 to mediate Th17 differentiation in Th17 predominant neutrophilic severe asthma. Clinical and experimental medicine 16 36961677

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