Affinage

MBD3

Methyl-CpG-binding domain protein 3 · UniProt O95983

Length
291 aa
Mass
32.8 kDa
Annotated
2026-06-10
67 papers in source corpus 30 papers cited in narrative 30 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MBD3 is a core scaffold subunit of the Mi-2/NuRD chromatin-remodeling and histone-deacetylase corepressor complex and an essential regulator of cell-fate commitment and early development (PMID:11274056, PMID:16462733, PMID:17287250). Unlike its paralog MBD2, the MBD3 methyl-CpG-binding domain carries atypical residues (His-30, Phe-34) that abolish high-affinity methylated-DNA binding; instead the MBD is necessary and sufficient for direct association with the NuRD components HDAC1 and MTA2, repurposing the methyl-reader fold into a complex-assembly module (PMID:12124384, PMID:30980593). MBD3 is the structural keystone of NuRD: in its absence the complex fails to assemble, ES cells acquire LIF-independent self-renewal and lose the ability to differentiate, and a Gatad2a-Chd4-Mbd3 subcomplex specifically blocks reacquisition of naive pluripotency (PMID:16462733, PMID:30122475). Genome-wide, MBD3 partitions to CpG-rich, H3K4me3-marked active and poised promoters and a subset of H3K27ac-marked enhancers, where together with the Brg1 remodeler it sets nucleosome occupancy and histone acetylation, and it is targeted to 5-hydroxymethylcytosine in a Tet1-dependent manner with preferential 5hmC over 5mC binding in cells (PMID:22196727, PMID:24385926). MBD3/NuRD is recruited to specific loci by sequence-specific factors — unphosphorylated c-Jun at AP-1 targets (relieved by JNK phosphorylation), PML-RARα, ZBTB7A/FBI-1 at CDKN1A, and Evi1 — to enforce deacetylation and, at some sites, DNA methylation and Polycomb mark deposition (PMID:21196933, PMID:18644863, PMID:23658227, PMID:18500823). MBD3 abundance is controlled post-translationally: Aurora-A phosphorylates it at M-phase centrosomes, GSK3β-dependent canonical Wnt signaling stabilizes it during neurogenesis, and the E3 ligases MKRN3, Smek, and TRIM59 (the last ubiquitinating K41/K90/K92) drive its degradation to derepress target programs (PMID:12354758, PMID:40750707, PMID:34692086, PMID:28467410, PMID:41982165). Through these activities MBD3/NuRD maintains H19 imprinting-control-region methylation, regulates rRNA-promoter methylation, and restricts chromatin accessibility at lineage-specific enhancers in lymphoid progenitors, with loss promoting tumorigenesis (PMID:17708683, PMID:17452452, PMID:28899870).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2000 Medium

    Established that MBD3 does not function as a solo methyl-reader but partners physically with MBD2 and the maintenance methyltransferase DNMT1 at replication foci, the first hint that its activity is coupled to other DNA-methylation machinery.

    Evidence Co-IP, in vitro binding, and replication-foci co-localization in mammalian cells

    PMID:10947852

    Open questions at the time
    • Functional consequence of the MBD2-MBD3 heterodimer at replication foci not established
    • Whether hemi-methylated DNA binding occurs in vivo unresolved
  2. 2001 High

    Defined MBD3 as a non-methyl-DNA-binding core subunit of the Mi-2/NuRD complex with an essential, MBD2-distinct role in embryogenesis, separating it functionally from its paralog.

    Evidence Knockout mice, biochemical fractionation, and Mbd2/Mbd3 double-mutant epistasis

    PMID:11274056

    Open questions at the time
    • Molecular basis of the loss of methyl-DNA binding not yet defined
    • Which NuRD activities require MBD3 specifically unaddressed
  3. 2002 High

    Explained the loss of methyl-CpG binding (His-30/Phe-34 substitutions) and reassigned the MBD3 MBD as a protein-interaction surface directly engaging HDAC1 and MTA2, redefining the domain's purpose as complex assembly.

    Evidence Recombinant binding assays, site-directed mutagenesis, co-IP, immunofluorescence

    PMID:12124384

    Open questions at the time
    • Restoring mCpG binding did not restore pericentromeric targeting, leaving the localization determinant unknown
  4. 2002 High

    Linked NuRD to the cell cycle by showing MBD3 is phosphorylated in G2/M and is an Aurora-A substrate at centrosomes, implying cell-cycle-regulated modulation of the complex.

    Evidence In vitro kinase assay, in vivo co-IP, and centrosomal co-localization

    PMID:12354758

    Open questions at the time
    • Functional consequence of Aurora-A phosphorylation on NuRD activity not determined
    • Phosphosite(s) unmapped
  5. 2006 High

    Resolved that MBD2 and MBD3 form mutually exclusive NuRD complexes and identified shared (DOC-1) versus MBD2-specific (PRMT5/MEP50) subunits, clarifying how the two paralogs build distinct repressive machines.

    Evidence Protein tagging, mass spectrometry, co-IP, and ChIP

    PMID:16428440

    Open questions at the time
    • MBD3-specific recruitment determinants not defined here
  6. 2007 High

    Demonstrated that MBD3 is the structural keystone for NuRD integrity and for exit from pluripotency, since its loss prevents complex assembly and differentiation while permitting LIF-independent self-renewal.

    Evidence Gene targeting, complex stability assays, differentiation/chimera assays, blastocyst outgrowth

    PMID:16462733 PMID:17287250

    Open questions at the time
    • Direct target genes mediating the differentiation block not enumerated
    • Mechanism of self-renewal gain unclear
  7. 2008 Medium

    Showed MBD3/NuRD is actively recruited by oncogenic and sequence-specific factors (PML-RARα) to facilitate layered repressive-mark deposition, positioning NuRD upstream of Polycomb and DNA methylation at silenced loci.

    Evidence Co-IP, ChIP, siRNA knockdown, expression analysis in APL models

    PMID:18644863

    Open questions at the time
    • Direct versus indirect contribution of MBD3 to H3K27me/DNA methylation not separated
  8. 2011 High

    Provided a signaling-gated recruitment paradigm: unphosphorylated c-Jun docks MBD3/NuRD at AP-1 targets and JNK phosphorylation evicts it, coupling NuRD repression to intestinal progenitor proliferation and tumor suppression.

    Evidence Co-IP, ChIP, conditional Mbd3 knockout, and c-Jun/Mbd3 genetic epistasis in vivo

    PMID:21196933

    Open questions at the time
    • Generality of phospho-switch recruitment to other transcription factors not tested here
  9. 2011 High

    Connected MBD3 to oxidized-cytosine biology, showing Tet1-dependent localization, preferential 5hmC binding, and Brg1-antagonistic control of nucleosome occupancy at active/poised genes.

    Evidence ChIP-seq, in vitro modified-DNA binding, Tet1-dependence, nucleosome occupancy assays

    PMID:22196727

    Open questions at the time
    • In vitro 5hmC preference reconciled only partially with later structural data
    • Direct readout versus Tet1-mediated indirect targeting not fully separated
  10. 2013 High

    Mapped MBD3 genome-wide to CpG-rich H3K4me3 promoters and H3K27ac enhancers in 3D-proximity to promoters, expanding its role from repressor to a regulator of active and enhancer chromatin architecture.

    Evidence DamID, ChIP-seq, chromatin conformation, nucleosome occupancy in two cell lines

    PMID:24385926

    Open questions at the time
    • Functional consequence of enhancer occupancy on target gene output not defined
  11. 2016 High

    Re-grounded MBD3 function in DNA methylation/hydroxymethylation by showing MBD2-MBD3 interdependence for chromatin binding and finding no methylation-independent functions, tempering claims of purely demethylation-driving roles.

    Evidence ES cell genetic knockouts, ChIP-seq, bisulfite and 5hmC profiling, expression analysis

    PMID:27849519

    Open questions at the time
    • Reconciliation with reports of MBD3-induced demethylation not resolved
  12. 2019 High

    Provided the structural basis for MBD3's weak methyl-DNA binding, showing arginine-finger-mediated mCG recognition and that the Phe34 substitution accounts for weaker, mCG-preferring (over hmCG) binding by the isolated MBD.

    Evidence X-ray crystallography of MBD3-MBD on mCG DNA, binding assays, mutagenesis

    PMID:30980593

    Open questions at the time
    • In vitro mCG-over-hmCG preference contrasts with cellular 5hmC association, leaving in vivo specificity unsettled
  13. 2020 High

    Established that MBD3 abundance and target recruitment are controlled by E3-ligase-driven ubiquitination, with MKRN3 disrupting MBD3 binding at GNRH1 and its recruitment of TET2 to time pubertal onset.

    Evidence Co-IP, ubiquitination assay, ChIP, knockout mice

    PMID:34692086

    Open questions at the time
    • Whether MBD3 directly recruits TET2 or acts via NuRD not dissected
    • Ubiquitination sites not mapped here
  14. 2017 High

    Showed context-dependent degradation (Smek) and chromatin-accessibility restriction by MBD3/NuRD govern cell-fate decisions, controlling cortical neurogenesis and lineage commitment in lymphoid progenitors with tumor-suppressive consequences.

    Evidence Co-IP, ubiquitination, ChIP, conditional knockouts, ATAC-seq, lineage tracing, epistasis rescue

    PMID:28467410 PMID:28899870

    Open questions at the time
    • Signals that trigger Smek-mediated degradation in vivo not fully defined
  15. 2025 Medium

    Added upstream signaling control of MBD3 stability, placing GSK3β/canonical Wnt as a regulator of MBD3 ubiquitination that tunes NuRD-mediated repression of neurogenic genes and NPC stemness.

    Evidence Wnt pathway modulation, ubiquitination assays, co-IP, expression analysis

    PMID:40750707

    Open questions at the time
    • Direct GSK3β substrate relationship versus indirect effect not resolved
    • Limited independent replication
  16. 2026 Medium

    Identified TRIM59 as an MBD3 E3 ligase that ubiquitinates the MBD at K41/K90/K92 to derepress HSF1/HSF2 and drive lung adenocarcinoma proliferation, mapping specific degradation sites.

    Evidence Co-IP, ubiquitination assay, MS site mapping, in vivo tumor models, tissue microarray

    PMID:41982165

    Open questions at the time
    • Whether the three ligases (MKRN3/Smek/TRIM59) act in distinct tissues/conditions not unified
    • Single-lab evidence

Open questions

Synthesis pass · forward-looking unresolved questions
  • How MBD3's in vitro mCG/5hmC binding properties, its phase-separation behavior, and its context-specific recruitment by diverse transcription factors and E3 ligases integrate into a single quantitative model of NuRD targeting in vivo remains unresolved.
  • No unified model reconciling cellular 5hmC association with structural mCG preference
  • Physiological role of MBD3 LLPS condensates untested in vivo
  • Tissue-specific logic of competing E3 ligases unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 4 GO:0060090 molecular adaptor activity 3 GO:0003677 DNA binding 2 GO:0042393 histone binding 1
Localization
GO:0000228 nuclear chromosome 2 GO:0005634 nucleus 2 GO:0005730 nucleolus 1 GO:0005815 microtubule organizing center 1
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-392499 Metabolism of proteins 3 R-HSA-4839726 Chromatin organization 3
Partners
CHD4GATAD2AHDAC1JUNMBD2MTA2TET1TRIM59
Complex memberships
Mi-2/NuRD complex

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 MBD3 fails to bind methylated DNA in murine cells and is a core component of the Mi-2/NuRD corepressor complex; Mbd3-/- mice die during early embryogenesis, demonstrating an essential developmental role distinct from MBD2. Genetic interaction between Mbd3 and Mbd2 was established by double-mutant analysis. Gene targeting (knockout mice), biochemical fractionation, genetic epistasis (double mutants) 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. MBD2, MBD3, and DNMT1 co-localize at replication foci in late S phase and form a complex by co-immunoprecipitation, suggesting a role in maintenance methylation. Co-immunoprecipitation, in vitro binding assays, immunofluorescence co-localization Genes to cells Medium 10947852
2002 The MBD of human MBD3 cannot bind mCpG due to atypical residues His-30 and Phe-34; mutating these to Lys/Tyr restores mCpG binding in vitro but does not restore pericentromeric localization in cells. The MBD of MBD3 is necessary and sufficient for direct binding to NuRD/Mi2 components HDAC1 and MTA2. Recombinant protein binding assays, site-directed mutagenesis, co-immunoprecipitation, immunofluorescence The Journal of biological chemistry High 12124384
2002 MBD3 is phosphorylated in vivo during late G2 and early M phase; Aurora-A kinase phosphorylates MBD3 in vitro, physically associates with MBD3 in vivo, and co-localizes with MBD3 and HDAC1 at centrosomes in early M phase, suggesting cell-cycle-regulated modification of the NuRD complex. FLAG-tagged MBD3 stable expression, co-immunoprecipitation, in vitro kinase assay, immunofluorescence The Journal of biological chemistry High 12354758
2002 Two p66 proteins (hp66alpha and hp66beta) directly bind both MBD2 and MBD3 and are components of the NuRD/Mi-2 complex; hp66alpha binds via two interaction domains while hp66beta uses one. Both are potent transcriptional repressors. Yeast two-hybrid, co-precipitation, confocal microscopy, transcriptional repression assays The Journal of biological chemistry Medium 12183469
2005 Dnmt3a purified from mouse lymphosarcoma cells co-purifies with Mbd3, HDAC1, and Brg1 complex components; GST pulldown shows that the ATRX homology domain of Dnmt3a interacts with the MBD of Mbd3. All three proteins occupy the methylated MT-I promoter by ChIP, and Mbd3 and Dnmt3a synergistically repress methylated promoters. Chromatographic purification, mass spectrometry, GST pulldown, co-immunoprecipitation, ChIP, transient transfection reporter assay Cancer research High 16322236
2006 MBD2 and MBD3 assemble into mutually exclusive NuRD-like complexes (MBD2/NuRD and MBD3/NuRD); DOC-1 is identified as a novel core subunit of both complexes; PRMT5 and MEP50 are specific MBD2/NuRD interactors that methylate MBD2's RG-rich N-terminus. By ChIP, PRMT5 and MBD2 are recruited to CpG islands in a methylation-dependent manner and H4R3 is methylated at these loci. Protein tagging, mass spectrometry, co-immunoprecipitation, ChIP Molecular and cellular biology High 16428440
2006 Mbd3-deficient ES cells fail to form a stable NuRD complex and are severely compromised in differentiation ability while exhibiting LIF-independent self-renewal, establishing Mbd3 as an essential scaffold for NuRD integrity and for cell fate commitment of pluripotent cells. Gene targeting, complex stability assays, differentiation assays (embryoid bodies, chimeric embryos), LIF withdrawal Nature cell biology High 16462733
2007 MBD3 binds to the H19 differentially methylated domain (DMD) by ChIP in preimplantation embryos; RNAi depletion of MBD3 activates paternal H19 expression, reduces DNA methylation at the H19 DMD, and reduces MTA-2 protein levels, demonstrating that MBD3/NuRD is required for maintaining imprinting control region methylation and silencing the paternal H19 allele. RNAi in mouse embryos, ChIP, bisulfite sequencing, allele-specific expression analysis, immunofluorescence PLoS genetics High 17708683
2007 MBD3 is localized to the nucleolus, colocalizes with upstream binding factor, and binds to unmethylated rRNA promoters. MBD3 knockdown causes increased methylation of the rRNA promoter, decreased RNA polymerase I binding, and reduced pre-rRNA transcription; MBD3 overexpression induces demethylation of methylated rRNA promoters including on non-replicating plasmids. siRNA knockdown, immunofluorescence, ChIP, bisulfite sequencing, plasmid demethylation assay Molecular and cellular biology Medium 17452452
2007 Mbd3 is required for proper gene expression patterns in pre- and peri-implantation embryos; the inner cell mass of Mbd3-deficient blastocysts fails to develop into mature epiblast, and Mbd3-null ICMs grown ex vivo fail to expand their Oct4-positive population, defining a developmental role for Mbd3/NuRD in pluripotent cell development in vivo. Gene targeting, blastocyst outgrowth assays, immunofluorescence, gene expression analysis Development High 17287250
2008 MBD3 overexpression induces DNA demethylation at specific genomic targets (preferentially promoter regions with intermediate CpG density), demonstrated by methylated DNA immunoprecipitation combined with promoter tiling microarray, establishing a causal role for MBD3 in DNA demethylation. MBD3 overexpression, methylated DNA immunoprecipitation (mDIP), promoter tiling microarray Gene Medium 18602768
2008 PML-RARα binds and recruits the NuRD complex (including MBD3) to target genes such as RARbeta2; NuRD facilitates Polycomb binding and H3K27 methylation at these loci. Knockdown of NuRD prevents histone deacetylation, chromatin compaction, DNA methylation, and histone methylation, establishing MBD3/NuRD as a facilitator of epigenetic repressive mark deposition in APL. Co-immunoprecipitation, ChIP, siRNA knockdown, gene expression analysis Molecular and cellular biology Medium 18644863
2008 Evi1 interacts with Mbd3b (but not other MBD family members) via its first three zinc fingers; the interaction domain on Mbd3 is the 40 amino acids adjacent to and downstream of the MBD. When Evi1 is present in the Mi-2/NuRD complex through Mbd3, it inhibits the histone deacetylation function of the complex in vitro. Yeast two-hybrid, in vitro and in vivo binding assays, in vitro HDAC activity assay, domain mapping Biochemistry Medium 18500823
2011 Unphosphorylated c-Jun interacts with Mbd3 to recruit the NuRD repressor complex to AP-1-dependent promoters; JNK-mediated N-terminal phosphorylation of c-Jun prevents Mbd3 binding and thereby relieves NuRD-mediated repression. Gut-specific deletion of Mbd3 increases histone acetylation at AP-1 target promoters, stimulates c-Jun activity, and increases progenitor proliferation; colitis-induced tumorigenesis is increased and reverted by c-Jun haploinsufficiency. Co-immunoprecipitation, ChIP, conditional knockout mice, genetic epistasis (c-Jun/Mbd3 double mutants) Nature High 21196933
2011 Mbd3 colocalizes with Tet1 and 5-hydroxymethylcytosine (5hmC) in vivo; Mbd3 localization is Tet1-dependent; Mbd3 preferentially binds 5hmC over 5-methylcytosine in vitro. Mbd3 knockdown preferentially affects expression of 5hmC-marked genes. Mbd3 and Brg1 antagonistically regulate promoter nucleosome occupancy at a common gene set. ChIP-seq, in vitro DNA binding assays, co-localization, shRNA knockdown, nucleosome occupancy assays Cell High 22196727
2013 FBI-1 (ZBTB7A) directly interacts with MBD3 in the nucleus; MBD3 is recruited to the CDKN1A promoter through FBI-1 interaction, recruits the Mi-2/NuRD-HDAC complex, and modulates FBI-1's co-repressor interactions (decreasing NCoR/SMRT interaction, increasing BCoR interaction). MBD3/NuRD facilitates recruitment of DNMTs and HP1 to mediate DNA methylation-based silencing of CDKN1A. Co-immunoprecipitation, ChIP, reporter assays, siRNA knockdown Nucleic acids research Medium 23658227
2013 MBD3 preferentially associates with CpG-rich promoters marked by H3K4me3 and regulates nucleosome occupancy near promoters and gene bodies; a subset of MBD3 binding sites is enriched in H3K27ac and is physically proximate to promoters in 3D space, suggesting enhancer function. DamID, ChIP-seq, chromatin conformation analysis, functional nucleosome occupancy assays PLoS genetics High 24385926
2015 MBD3 adopts a salt-dependent homodimeric association with chromatin target loci in G1 phase, as determined by single-molecule fluorescence spectroscopy; a proportion of MBD3 co-localizes with MBD2 and DNMT1 during S-phase maintenance methylation. MBD3 siRNA knockdown results in global DNA hypermethylation and increased promoter CpG island methylation. Fluorescence lifetime correlation spectroscopy (FLCS), photon counting histogram, FLIM-FRET, siRNA knockdown, bisulfite sequencing Nucleic acids research Medium 25753672
2016 Mbd2 and Mbd3 are interdependent for chromatin association in ES cells; both are required for normal levels of cytosine methylation and hydroxymethylation; Mbd2 and Mbd3 regulate overlapping gene sets also regulated by DNA methylation/hydroxymethylation factors. No evidence for methylation-independent functions was found. ChIP-seq, genetic knockouts, bisulfite sequencing, 5hmC profiling, gene expression analysis eLife High 27849519
2017 Smek interacts with Mbd3 and promotes its polyubiquitylation and proteasomal degradation; Smek-mediated degradation of Mbd3 blocks recruitment of the repressive Mbd3/NuRD complex at neurogenesis-associated gene loci, increases acetyl-H3 activity, and promotes cortical neurogenesis. Mbd3 depletion rescues neurogenesis defects in Smek1/2 knockout mice. Co-immunoprecipitation, ubiquitination assays, ChIP, genetic epistasis (Smek KO + Mbd3 KD), in vivo cortical neurogenesis assays PLoS biology High 28467410
2017 Mbd3/NuRD restricts chromatin accessibility at B cell enhancers and promoters in lymphoid progenitors; Mbd3/NuRD-deficient lymphoid progenitors prematurely activate a B cell transcriptional program with bias toward pro-B cell production at the expense of T cell progenitors, leading to T cell lymphoma. Conditional knockout mice, ATAC-seq/chromatin accessibility assays, lineage tracing, flow cytometry The Journal of experimental medicine High 28899870
2018 A specific Mbd3/NuRD subcomplex containing Gatad2a-Chd4-Mbd3 is critical for blocking reestablishment of naive pluripotency; Gatad2a deletion specifically disrupts Mbd3/NuRD repressive activity on the pluripotency circuitry without ablating somatic cell proliferation. Post-translational modifications and signaling-dependent assembly of Mbd3/NuRD influence its interactions. Genetic knockouts, co-immunoprecipitation, iPSC reprogramming assays, complex assembly analysis Cell stem cell High 30122475
2018 The C-terminal D/E-rich domain of MBD3 acts as a DNA mimic to compete with Z-DNA for binding to the Zα domain of ADAR1; MBD3 and ADAR1 interact in vivo by co-immunoprecipitation. Dimerization of MBD3 via intermolecular interaction of the D/E-rich domain and MBD attenuates Zα binding. Pulldown, biophysical analysis, co-immunoprecipitation, DNA conformation assays Nucleic acids research Medium 30304469
2019 Crystal structure of MBD3-MBD bound to mCG-containing DNA reveals that binding occurs through two conserved arginine fingers; the tyrosine-to-phenylalanine substitution at Phe34 of MBD3 (vs. MBD2) is responsible for weaker mCG binding. MBD3-MBD binds mCG over hmCG with preference, and mCG binding by MBD2/3 family members across metazoans requires conserved arginine fingers and structural fold. X-ray crystallography, in vitro DNA binding assays, mutagenesis The FEBS journal High 30980593
2019 MBD3 is preferentially expressed in glioma stem-like cells (GSCs) and recruits the NuRD complex to the STAT1 promoter to suppress STAT1 expression via histone deacetylation; MBD3 depletion or STAT1 overexpression induces p21 transcription, resensitizes GSCs to type I interferon suppression, and attenuates tumor growth. ChIP, siRNA knockdown, overexpression, co-immunoprecipitation, in vivo tumor models The Journal of experimental medicine High 32181805
2020 MKRN3 (an E3 ubiquitin ligase) interacts with and ubiquitinates MBD3; MKRN3-mediated ubiquitination disrupts MBD3 binding to the GNRH1 promoter and MBD3 recruitment of DNA demethylase TET2, thereby controlling epigenetic silencing of GNRH1 and the onset of puberty. Co-immunoprecipitation, ubiquitination assay, ChIP, genetic knockout mice National science review High 34692086
2025 Canonical Wnt signaling regulates Mbd3 protein stability: Wnt3a activator and DKK1 inhibitor modulate Mbd3 expression in parallel with β-catenin; GSK3β overexpression promotes and depletion attenuates Mbd3 ubiquitination. Downstream of Wnt-β-catenin, Mbd3 represses neurogenesis-associated gene transcription by triggering NuRD complex assembly, thereby promoting NPC stemness. Wnt pathway modulation (Wnt3a, DKK1, GSK3β overexpression/depletion), ubiquitination assays, co-immunoprecipitation, gene expression analysis Experimental & molecular medicine Medium 40750707
2026 TRIM59 functions as an E3 ubiquitin ligase for MBD3; TRIM59 physically associates with the N-terminal MBD domain of MBD3 and catalyzes its polyubiquitination and degradation at lysine residues K41, K90, and K92 (mapped by mass spectrometry). TRIM59-mediated MBD3 degradation derepresses HSF1 and HSF2, driving proliferation in lung adenocarcinoma. Co-immunoprecipitation, ubiquitination assay, mass spectrometry site mapping, in vivo tumor models, tissue microarray Acta biochimica et biophysica Sinica Medium 41982165
2025 MBD2 and MBD3 undergo liquid-liquid phase separation (LLPS) with distinct mechanisms despite high sequence identity; MBD3 shows different residue patterns driving distinct homotypic and heterotypic interactions. DNA influences MBD2/MBD3 LLPS, suggesting condensate-mediated organization of heterochromatin. Integrated computational and experimental approach (in vitro LLPS assays, molecular simulations) The journal of physical chemistry B Medium 40350613

Source papers

Stage 0 corpus · 67 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 Closely related proteins MBD2 and MBD3 play distinctive but interacting roles in mouse development. Genes & development 394 11274056
2011 Mbd3/NURD complex regulates expression of 5-hydroxymethylcytosine marked genes in embryonic stem cells. Cell 365 22196727
2006 The NuRD component Mbd3 is required for pluripotency of embryonic stem cells. Nature cell biology 306 16462733
2006 MBD2/NuRD and MBD3/NuRD, two distinct complexes with different biochemical and functional properties. Molecular and cellular biology 271 16428440
2002 The mCpG-binding domain of human MBD3 does not bind to mCpG but interacts with NuRD/Mi2 components HDAC1 and MTA2. The Journal of biological chemistry 143 12124384
2007 Mbd3, a component of the NuRD co-repressor complex, is required for development of pluripotent cells. Development (Cambridge, England) 140 17287250
2014 MBD3/NuRD facilitates induction of pluripotency in a context-dependent manner. Cell stem cell 137 24835571
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
2011 c-Jun N-terminal phosphorylation antagonises recruitment of the Mbd3/NuRD repressor complex. Nature 109 21196933
2008 MBD3, a component of the NuRD complex, facilitates chromatin alteration and deposition of epigenetic marks. Molecular and cellular biology 92 18644863
2013 MBD3 localizes at promoters, gene bodies and enhancers of active genes. PLoS genetics 91 24385926
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
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
2020 MKRN3 regulates the epigenetic switch of mammalian puberty via ubiquitination of MBD3. National science review 68 34692086
2007 Maintenance of paternal methylation and repression of the imprinted H19 gene requires MBD3. PLoS genetics 64 17708683
2018 Neutralizing Gatad2a-Chd4-Mbd3/NuRD Complex Facilitates Deterministic Induction of Naive Pluripotency. Cell stem cell 63 30122475
2005 Physical and functional interaction of DNA methyltransferase 3A with Mbd3 and Brg1 in mouse lymphosarcoma cells. Cancer research 56 16322236
2014 MBD2 and MBD3: elusive functions and mechanisms. Frontiers in genetics 55 25538734
2007 Epigenetic programming of the rRNA promoter by MBD3. Molecular and cellular biology 50 17452452
2002 MBD3 and HDAC1, two components of the NuRD complex, are localized at Aurora-A-positive centrosomes in M phase. The Journal of biological chemistry 47 12354758
2020 Glioma stem-like cells evade interferon suppression through MBD3/NuRD complex-mediated STAT1 downregulation. The Journal of experimental medicine 45 32181805
2019 Disruption of the MBD2-NuRD complex but not MBD3-NuRD induces high level HbF expression in human adult erythroid cells. Haematologica 45 31004025
2013 The proto-oncoprotein FBI-1 interacts with MBD3 to recruit the Mi-2/NuRD-HDAC complex and BCoR and to silence p21WAF/CDKN1A by DNA methylation. Nucleic acids research 42 23658227
2009 Mbd3, a component of NuRD/Mi-2 complex, helps maintain pluripotency of mouse embryonic stem cells by repressing trophectoderm differentiation. PloS one 39 19888462
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
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
2008 DNA demethylation induced by the methyl-CpG-binding domain protein MBD3. Gene 30 18602768
2015 Dissecting the behavior and function of MBD3 in DNA methylation homeostasis by single-molecule spectroscopy and microscopy. Nucleic acids research 27 25753672
2017 Smek promotes corticogenesis through regulating Mbd3's stability and Mbd3/NuRD complex recruitment to genes associated with neurogenesis. PLoS biology 25 28467410
2016 DNA methylation directs genomic localization of Mbd2 and Mbd3 in embryonic stem cells. eLife 25 27849519
2019 MBD3/NuRD loss participates with KDM6A program to promote DOCK5/8 expression and Rac GTPase activation in human acute myeloid leukemia. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 24 30668141
2017 Mbd3/NuRD controls lymphoid cell fate and inhibits tumorigenesis by repressing a B cell transcriptional program. The Journal of experimental medicine 24 28899870
2022 MBD3 promotes hepatocellular carcinoma progression and metastasis through negative regulation of tumour suppressor TFPI2. British journal of cancer 23 35501390
2016 MBD3 mediates epigenetic regulation on EPAS1 promoter in cancer. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 23 27465550
2008 Myeloid transforming protein Evi1 interacts with methyl-CpG binding domain protein 3 and inhibits in vitro histone deacetylation by Mbd3/Mi-2/NuRD. Biochemistry 21 18500823
2019 Structural analyses reveal that MBD3 is a methylated CG binder. The FEBS journal 19 30980593
2019 Histone deacetylases, Mbd3/NuRD, and Tet2 hydroxylase are crucial regulators of epithelial-mesenchymal plasticity and tumor metastasis. Oncogene 19 31666683
2003 Differential expression of methyl CpG-binding domain containing factor MBD3 in the developing and adult rat brain. Journal of neurobiology 19 12672019
2016 MiR-134-Mbd3 axis regulates the induction of pluripotency. Journal of cellular and molecular medicine 17 26929159
2004 Xenopus MBD3 plays a crucial role in an early stage of development. Developmental biology 15 15063177
2017 MBD3 inhibits formation of liver cancer stem cells. Oncotarget 14 27894081
2014 Construction of eukaryotic expression vector with mBD1-mBD3 fusion genes and exploring its activity against influenza A virus. Viruses 13 24632574
2004 Genetic and epigenetic analyses of MBD3 in colon and lung cancer. British journal of cancer 13 15138480
2024 MBD3 promotes epithelial-mesenchymal transition in gastric cancer cells by upregulating ACTG1 via the PI3K/AKT pathway. Biological procedures online 11 38178023
2021 Functional Analysis of Non-Genetic Resistance to Platinum in Epithelial Ovarian Cancer Reveals a Role for the MBD3-NuRD Complex in Resistance Development. Cancers 11 34359703
2013 Removing reprogramming roadblocks: Mbd3 depletion allows deterministic iPSC generation. Cell stem cell 11 24094318
2023 MBD3 as a Potential Biomarker for Colon Cancer: Implications for Epithelial-Mesenchymal Transition (EMT) Pathways. Cancers 10 37370795
2018 The C-terminal D/E-rich domain of MBD3 is a putative Z-DNA mimic that competes for Zα DNA-binding activity. Nucleic acids research 10 30304469
2019 Overexpression of MBD3 Improves Reprogramming of Cloned Pig Embryos. Cellular reprogramming 7 31393170
2018 Mbd3 Promotes Reprogramming of Primary Human Fibroblasts. International journal of stem cells 7 30497130
2016 MBD3 expression and DNA binding patterns are altered in a rat model of temporal lobe epilepsy. Scientific reports 7 27650712
2016 Regulatory landscape and clinical implication of MBD3 in human malignant glioma. Oncotarget 7 27835581
2020 Methyl-CpG-binding domain 3 (Mbd3) is an important regulator for apoptosis in mouse embryonic stem cells. American journal of translational research 6 33437388
2025 Uncovering the Molecular Interactions Underlying MBD2 and MBD3 Phase Separation. The journal of physical chemistry. B 5 40350613
2022 Nucleosome remodeling and deacetylation complex and MBD3 influence mouse embryonic stem cell naïve pluripotency under inhibition of protein kinase C. Cell death discovery 5 35915078
2016 High-quality ChIP-seq analysis of MBD3 in human breast cancer cells. Genomics data 5 26981404
2020 Thyroid hormone activates Xenopus MBD3 gene via an intronic TRE in vivo. Frontiers in bioscience (Landmark edition) 4 31585895
2025 LncRNA16 inhibits pyroptosis and promotes platinum resistance in non-small cell lung cancer by sponging miRNA1827 to regulate MBD3/GSDME expression. Cancer cell international 3 40413520
2009 MBD3 mutations are not responsible for ICR1 hypomethylation in Silver-Russell syndrome. European journal of medical genetics 3 20004753
2024 Uncovering the molecular interactions underlying MBD2 and MBD3 phase separation. bioRxiv : the preprint server for biology 2 38746378
2021 Expression of mBD4, mBD3 and CRAMP during type II collagen-induced arthritis/CIA and their association with inflammation and bone-remodeling markers. Experimental and molecular pathology 2 34592200
2025 Canonical Wnt signaling regulates Mbd3 protein stability during neurogenesis. Experimental & molecular medicine 1 40750707
2025 The role of Methyl-CpG binding domain 3 (Mbd3) protein in epileptogenesis. PloS one 1 41060926
2023 Clinical significance of serum MBD3 detection in girls with central precocious puberty. Open medicine (Warsaw, Poland) 1 37426049
2026 MBD3 increased expression by BRD4 and facilitated castration-resistant prostate cancer cell proliferation by inhibiting PTEN. Discover oncology 0 41663664
2026 The role of MBD3 in cell biology and disease: Recent advances and future directions. Experimental cell research 0 41933571
2026 Ubiquitin-dependent degradation of MBD3 by TRIM59 promotes lung adenocarcinoma. Acta biochimica et biophysica Sinica 0 41982165

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