Affinage

MBNL1

Muscleblind-like protein 1 · UniProt Q9NR56

Length
388 aa
Mass
41.8 kDa
Annotated
2026-04-28
100 papers in source corpus 37 papers cited in narrative 37 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MBNL1 is a CCCH zinc-finger RNA-binding protein that orchestrates developmentally programmed alternative splicing transitions across multiple tissues, while also regulating mRNA stability and nuclear export of repeat-containing transcripts. MBNL1 recognizes YGCY motifs in pre-mRNA introns and 3′ UTRs through its tandem zinc-finger pairs, which bind GC dinucleotides in looped RNA segments; an ~80 amino-acid segment downstream of the N-terminal zinc fingers constitutes the core splicing-regulatory effector domain that is separable from RNA binding (PMID:20071745, PMID:19043415, PMID:21109529). MBNL1 represses or activates exon inclusion depending on binding position relative to the regulated exon, acting through competition with U2AF65 at 3′ splice sites and cooperation with PTB; it also promotes mRNA decay of 3′ UTR-bound transcripts, stabilizes differentiation-specific mRNAs, and autoregulates its own expression through splicing of exons 1 and 5 (PMID:19470458, PMID:23511971, PMID:22355723, PMID:21832083, PMID:27903900). Sequestration of MBNL1 by expanded CUG/CCUG repeat RNAs in nuclear foci underlies the mis-splicing and multisystem pathology of myotonic dystrophy types 1 and 2 (PMID:15546872, PMID:16717059).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2004 High

    Establishing that MBNL1 is the critical splicing regulator whose sequestration drives DM1 pathogenesis resolved a long-standing question about whether CUG repeat toxicity operates through protein loss-of-function; siRNA knockdown of MBNL1 in normal cells recapitulated DM1 mis-splicing while MBNL1 rescue in DM1 cells corrected it.

    Evidence siRNA knockdown and overexpression rescue in DM1 myoblasts with IR exon 11 splicing readout

    PMID:15546872

    Open questions at the time
    • Downstream effectors linking IR mis-splicing to insulin resistance not fully delineated
    • Relative contributions of MBNL1 vs. MBNL2 loss to specific DM1 symptoms not separated
  2. 2004 Medium

    Defining the RNA-binding specificity of MBNL1 for CHHG/CHG motifs in structured RNAs established why it is selectively sequestered by CUG/CCUG expansions and revealed a preference for bulge-containing rather than perfectly base-paired RNA.

    Evidence Yeast three-hybrid system with systematic RNA variants

    PMID:14722159

    Open questions at the time
    • Binding quantitation in physiological ionic conditions not reported
    • Specificity contributions of individual zinc fingers not resolved
  3. 2006 High

    Demonstrating that MBNL1 controls postnatal developmental splicing switches in skeletal muscle — and that its nuclear translocation coincides with these transitions — established MBNL1 as a master regulator of the fetal-to-adult splicing program, explaining why its sequestration reverts adult tissues to fetal splicing patterns.

    Evidence MBNL1 knockout mice with RT-PCR splicing analysis across postnatal development, immunofluorescence localization

    PMID:16717059

    Open questions at the time
    • Signals triggering postnatal MBNL1 nuclear translocation not identified
    • Whether MBNL1 controls splicing transitions in non-muscle tissues during development not addressed
  4. 2008 High

    The crystal structure of MBNL1 ZnF3/4 bound to RNA revealed the atomic basis for GC-step recognition through main-chain hydrogen bonds and showed that antiparallel binding geometry forces RNA into a chain-reversal loop, providing a structural explanation for how MBNL1 recognizes looped RNA near splice junctions.

    Evidence X-ray crystallography of ZnF3/4–r(CGCUGU) complex

    PMID:19043415

    Open questions at the time
    • Structure of full-length MBNL1 or ZnF1/2 pair with RNA not determined
    • How the chain-reversal loop geometry translates into splicing repression or activation not mechanistically resolved
  5. 2009 High

    Showing that MBNL1 competes directly with U2AF65 for binding at the 3′ splice site of cTNT intron 4 — with MBNL1 stabilizing a stem-loop structure that occludes the U2AF65 binding site — established the first complete mechanistic model for MBNL1-mediated exon skipping.

    Evidence In vitro RNA binding competition, RNA structure probing, splicing reporter assays

    PMID:19470458

    Open questions at the time
    • Whether this U2AF65 competition mechanism generalizes to all MBNL1-repressed exons not tested
    • Role of spliceosomal components downstream of U2AF65 not examined
  6. 2010 High

    SELEX identification and functional validation of the YGCY consensus motif unified MBNL1 RNA recognition into a single sequence code and showed that binding position relative to the regulated exon determines whether MBNL1 activates or represses inclusion, establishing an RNA-map framework.

    Evidence Doped SELEX, minigene reporter assays with inserted YGCY motifs

    PMID:20071745

    Open questions at the time
    • Quantitative RNA-map across the transcriptome not yet generated
    • How local RNA structure modulates YGCY motif accessibility not systematically addressed
  7. 2010 High

    Domain dissection revealed that the splicing-regulatory activity of MBNL1 maps to an ~80 amino-acid segment downstream of the N-terminal zinc-finger pair, separable from RNA-binding, establishing that MBNL1 uses distinct domains for substrate recognition and spliceosome modulation.

    Evidence Sequential deletion analysis with splicing reporter and RNA binding assays for IR and cTNT minigenes

    PMID:21109529

    Open questions at the time
    • Protein partners recruited by the regulatory domain not identified
    • Whether this domain mediates direct spliceosome contacts not tested
  8. 2011 High

    Discovery that MBNL1 autoregulates by binding its own intron 4 to suppress exon 5 inclusion established a negative feedback loop controlling MBNL1 isoform levels, and later work showed exon 1 autoregulation controls protein stability and translation.

    Evidence Minigene reporter, RNA footprinting, deletion mutagenesis (exon 5); CLIP-seq, polysome profiling (exon 1)

    PMID:21832083 PMID:27903900

    Open questions at the time
    • Quantitative contribution of each autoregulatory circuit to steady-state MBNL1 levels not modeled
    • Whether autoregulation is disrupted in DM tissues not directly tested
  9. 2012 Medium

    CLIP analysis revealed that MBNL1 preferentially binds 3′ UTRs genome-wide and promotes mRNA decay, expanding its functional repertoire beyond alternative splicing to post-transcriptional regulation of mRNA stability.

    Evidence In vivo CLIP, expression arrays, RT-PCR validation

    PMID:22355723

    Open questions at the time
    • Mechanism of MBNL1-mediated mRNA decay (deadenylation, decapping) not identified
    • Whether 3′ UTR binding and splicing regulation are coordinated on the same transcripts not addressed
  10. 2013 High

    Demonstration that MBNL1 cooperates with PTB through direct protein–protein contact to co-repress Tpm1 exon 3 — with RNA binding allosterically enhancing this interaction — established a cooperative co-regulatory mechanism beyond simple competition models.

    Evidence Minigene splicing reporter, protein pulldown, single-molecule FRET/imaging

    PMID:23511971

    Open questions at the time
    • Structural basis of MBNL1–PTB interaction not determined
    • How widespread MBNL1–PTB cooperativity is across the transcriptome not assessed
  11. 2014 Medium

    Identification of two NLS classes in MBNL1 — a bipartite and a conformational NLS switched by alternative splicing of exon 7 — explained how MBNL1 subcellular distribution is dynamically controlled and linked nuclear MBNL1 to suppression of RAN translation from expanded repeats.

    Evidence NLS mutagenesis, subcellular fractionation, immunofluorescence, RAN translation reporter

    PMID:25274774

    Open questions at the time
    • Kinases or other modifiers controlling NLS accessibility not identified
    • Whether NLS switching occurs in response to developmental cues in vivo not shown
  12. 2017 Medium

    Discovery that K63-linked polyubiquitination retains MBNL1 in the cytoplasm — and that expanded CUG RNA induces its deubiquitination and nuclear translocation — revealed a post-translational regulatory layer controlling MBNL1 compartmentalization.

    Evidence K63-specific ubiquitination assays, subcellular fractionation, neurite morphology assays, DM1 mouse brain analysis

    PMID:29490267

    Open questions at the time
    • E3 ligase and deubiquitinase acting on MBNL1 not identified
    • Whether K63-Ub regulation operates in non-neuronal tissues not tested
  13. 2018 Medium

    Showing that MBNL1 exon 7 inclusion is required for homodimerization and that Δex7 isoforms act as dominant negatives causing DNA damage revealed that dimerization is functionally essential and that isoform imbalance can be pathogenic.

    Evidence Splice-switching ASOs, co-immunoprecipitation, cell viability and migration assays

    PMID:30456384

    Open questions at the time
    • Structure of MBNL1 dimer not determined
    • Whether dominant-negative effects occur at physiological Δex7 isoform ratios not established
  14. 2020 Medium

    Multiple studies expanded MBNL1's tissue roles to thymus development, erythropoiesis, cancer stem cell maintenance, and vascular smooth muscle cell transdifferentiation, each linked to specific mis-spliced target genes (TCF/LEF, Ndel1, MAP2K7, Abi1), establishing MBNL1 as a broadly acting differentiation regulator across lineages.

    Evidence Mbnl1 knockout mice (thymus), knockdown in erythroid progenitors, knockdown/overexpression in cancer cells and VSMCs, RNA-seq, pharmacological epistasis

    PMID:24869935 PMID:32332745 PMID:32601196 PMID:33759281

    Open questions at the time
    • Whether MBNL1 loss-of-function effects in these tissues are all splice-mediated or partially through mRNA stability not resolved
    • Degree of functional redundancy with MBNL2 in each lineage not systematically assessed
  15. 2022 High

    In the heart, MBNL1 was shown to control the postnatal hyperplastic-to-hypertrophic growth switch and cardiomyocyte maturation, while combined MBNL1/MBNL2 ablation in cardiomyocytes caused lethal arrhythmia with DM-like spliceopathy, directly linking MBNL activity to cardiac pathophysiology.

    Evidence Gain- and loss-of-function mouse models, multi-omics, cardiac-specific double-KO with electrophysiology

    PMID:35567413 PMID:38426339

    Open questions at the time
    • Specific mis-spliced transcripts causally responsible for arrhythmia not definitively identified
    • Whether graded MBNL1 dosage produces distinct cardiac phenotypes not tested
  16. 2022 High

    MBNL1 was established as a driver of fibroblast-to-myofibroblast transitions critical for cardiac wound healing and scar maturation, with its loss enabling fibroblasts to acquire mesenchymal stem cell features.

    Evidence Fibroblast- and myofibroblast-specific mouse models with cardiac injury, transcriptomic profiling

    PMID:35176223

    Open questions at the time
    • Direct MBNL1 splicing targets mediating myofibroblast specification not fully cataloged
    • Whether MBNL1 drives fibrosis in non-cardiac tissues through the same mechanism not tested
  17. 2023 Medium

    Discovery that MBNL1 loss upregulates MBNL2 through a splicing-mediated compensation mechanism — increasing Mbnl2 exon 9 inclusion to remove a PEST degradation signal — revealed cross-paralog feedback that complicates interpretation of single-gene knockouts.

    Evidence RT-PCR, MBNL1 knockout mouse tissues, protein stability assays, MBNL2 localization assays

    PMID:36617982

    Open questions at the time
    • Whether MBNL2 similarly regulates MBNL1 not tested
    • Quantitative degree to which compensation masks MBNL1 loss phenotypes in vivo not determined

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the identity of the E3 ubiquitin ligase and deubiquitinase governing MBNL1 cytoplasmic retention; the structural basis of full-length MBNL1 dimerization and its interaction with the spliceosome; and the mechanistic basis distinguishing MBNL1's roles in mRNA decay versus splicing on shared target transcripts.
  • E3 ligase/DUB for K63-Ub of MBNL1 unknown
  • Full-length MBNL1 structure not determined
  • Mechanism coupling 3′ UTR binding to mRNA decay machinery uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 5 GO:0098772 molecular function regulator activity 3 GO:0140098 catalytic activity, acting on RNA 1
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 2
Pathway
R-HSA-8953854 Metabolism of RNA 8 R-HSA-1266738 Developmental Biology 4 R-HSA-1643685 Disease 3
Partners
DDX1DDX5MBNL2PTBRBFOX2U2AF65YB1

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 MBNL1 controls a set of developmentally regulated alternative splicing switches in skeletal muscle that occur postnatally (P2–P20). During this interval MBNL1 translocates from predominantly cytoplasmic to nuclear distribution. In the absence of MBNL1 (knockout mice), these physiological splicing transitions fail to occur, reproducing the splicing defects of DM1. Transgenic mouse models, MBNL1 knockout mice, RT-PCR splicing assays, immunofluorescence localization Human molecular genetics High 16717059
2004 MBNL1 is the primary determinant of DM1 nuclear RNA focus integrity and aberrant insulin receptor (IR) exon 11 splicing. siRNA-mediated knockdown of MBNL1 in normal myoblasts recapitulates DM1-like IR mis-splicing; rescue of MBNL1 in DM1 myoblasts corrects focus formation and IR splicing. CUG-BP antagonizes MBNL1/MBNL2 facilitatory activity on IR exon 11 inclusion in a dose-dependent manner. siRNA knockdown, overexpression rescue experiments in DM1 myoblasts, RT-PCR splicing assay The Journal of biological chemistry High 15546872
2004 MBNL1 specifically binds CHHG and CHG repeat RNA motifs (including CUG and CCUG repeats). MBNL1 does not bind canonical double-stranded CAG/CUG RNA but prefers bulge-containing double-stranded RNAs. Deletion analysis shows differences in RNA-binding ability among MBNL1 splice variants. Yeast three-hybrid system, synthetic RNA binding assays Human molecular genetics Medium 14722159
2008 Crystal structure of MBNL1 ZnF3/4 bound to r(CGCUGU) reveals that both zinc fingers target GC steps via hydrogen bonds formed primarily with main-chain groups. The antiparallel orientation of bound GC elements is dictated by the interdomain linker topology, supporting a chain-reversal loop trajectory for MBNL1-bound pre-mRNA, suggesting that MBNL1 targets looped RNA segments proximal to splice-site junctions. X-ray crystallography Nature structural & molecular biology High 19043415
2010 MBNL1 binds YGCY (pyrimidine-GC-pyrimidine) motifs to regulate alternative splicing. SELEX on a known MBNL1 binding site identified pyrimidine-rich RNAs with YGCY motifs; insertion of multiple YGCY motifs into a normally MBNL1-independent splicing reporter conferred MBNL1 regulation. YGCY motifs in introns downstream of MBNL1-repressed exons and upstream of MBNL1-activated exons explain position-dependent regulation. Doped SELEX, splicing reporter minigene assays, RT-PCR Nucleic acids research High 20071745
2009 MBNL1 controls splicing of cardiac troponin T (cTNT) exon 5 by competing directly with the essential splicing factor U2AF65 for binding at the 3′ end of intron 4. MBNL1 binds a stem-loop form of the intron, whereas U2AF65 binds the same region in single-stranded form; when U2AF65 binding is blocked, U2 snRNP cannot be recruited and the downstream exon is skipped. In vitro RNA binding assays, splicing reporter assays, RNA structure probing, competition binding Proceedings of the National Academy of Sciences of the United States of America High 19470458
2012 MBNL1 preferentially binds 3′ UTRs genome-wide and mediates accelerated mRNA decay of a broad spectrum of mRNAs, in addition to its known role in alternative splicing regulation. In vivo CLIP, expression arrays, RT-PCR validation Scientific reports Medium 22355723
2011 MBNL1 autoregulates its own pre-mRNA: it binds within intron 4 (between the distant branch point and 3′ splice site) of its own transcript, suppressing inclusion of exon 5. Structure probing and footprinting showed the conserved binding region is primarily unstructured; deletion of the MBNL1 response element eliminated autoregulation. Minigene splicing reporter, RNA structure probing, footprinting, deletion mutagenesis The Journal of biological chemistry High 21832083
2010 Mbnl1 promotes insulin receptor exon 11 inclusion via binding to a downstream evolutionarily conserved intronic splicing enhancer in intron 11. RNA affinity chromatography identified Mbnl1 as the binding factor; RNP immunoprecipitation confirmed binding to INSR RNA; overexpression or knockdown of Mbnl1 altered exon 11 inclusion; deletion of the enhancer eliminated Mbnl1-dependent regulation. RNA affinity chromatography, RNP immunoprecipitation, minigene deletion mutagenesis, knockdown/overexpression The Journal of biological chemistry High 20519504
2010 The four CCCH zinc fingers of MBNL1 provide a flexible platform for RNA recognition: a single GC dinucleotide in poly-U is sufficient for binding, a second GC confers higher affinity, but additional GCs do not further enhance binding. The distance between two GC dinucleotides can vary from 1 to 17 nt for high-affinity binding, suggesting MBNL1 adopts different conformations. Systematic RNA binding assays (filter binding, fluorescence anisotropy) BMC molecular biology Medium 21548961
2010 Regions required for splicing regulation by MBNL1 and MBNL3 are separate from the zinc-finger RNA-binding domains: an ~80 amino-acid segment downstream of the N-terminal ZnF pair contains core regulatory regions for both splicing activation and repression. Deletions in this region abolished regulation without preventing RNA binding. Sequential deletion analysis, splicing reporter assays (IR exon 11 and cTNT exon 5 minigenes), RNA binding assays Nucleic acids research High 21109529
2008 MBNL1 associates with YB-1 and DDX1 in cytoplasmic stress granules. GST pull-down identified YB-1 and DDX1 as MBNL1-interacting proteins; upon stress, MBNL1 relocates from nucleus to cytoplasmic stress granules where it co-localizes with YB-1 and DDX1. GST pull-down, co-immunofluorescence, stress granule induction Journal of neuroscience research Medium 18335541
2011 The RNA helicase p68/DDX5 associates with MBNL1 on CUG repeat RNA and on the cTNT pre-mRNA regulatory stem-loop; p68 increases MBNL1 binding to these substrates by remodeling RNA secondary structure. Mutations in the p68 helicase core abolished both the stimulatory effect on MBNL1 binding and colocalization with CUG foci. In vitro CUG repeat pulldown, co-localization assays, binding enhancement assays, helicase-dead mutant analysis Nucleic acids research Medium 22156369
2012 MBNL1 zinc finger pairs have differential RNA affinity and differential splicing activities. Combinatorial ZF mutagenesis identified two distinct classes of MBNL1 pre-mRNA substrates distinguished by their ZF requirements; for some transcripts splicing activity was dissociated from RNA binding. Combinatorial zinc finger mutagenesis, splicing reporter assays, RNA binding assays Molecular and cellular biology Medium 22890842
2013 MBNL1 and PTB cooperate to repress Tpm1 exon 3 splicing: MBNL1 binds UGC/CUG cluster motifs near exon 3 as a repressor, the N-terminal CCCH ZnF region of MBNL1 is sufficient for repression, MBNL1 makes direct protein-protein contact with PTB, and RNA binding by MBNL1 promotes this interaction (allosteric conformational change). Single-molecule analysis showed MBNL-binding sites increase PTB binding. Minigene splicing reporter assays, protein-protein pulldown, RNA-protein binding assays, single-molecule FRET/imaging Nucleic acids research High 23511971
2013 MBNL1 and RBFOX2 cooperate to control a splicing programme governing pluripotent stem cell differentiation into mesoderm; approximately half of MBNL1-controlled splicing events are co-regulated by RBFOX2. High-throughput RT-PCR, knockdown experiments in iPSCs and fibroblasts Nature communications Medium 24048253
2014 MBNL1 directly binds and regulates a network of differentiation-specific mRNAs (including SRF and calcineurin Aβ 3′ UTRs) to promote myofibroblast differentiation. CRISPR-Cas9 editing of the MBNL1-binding site within the Srf 3′ UTR impairs myofibroblast differentiation; in vivo deletion of Srf in fibroblasts impairs wound healing. Genome-wide loss-of-function screen, RIP assays, CRISPR-Cas9 editing of binding sites, mouse wound-healing models Nature communications High 26670661
2014 Nuclear localization of MBNL1 is controlled by two classes of NLS: a classical bipartite NLS and a novel conformational NLS. Alternative splicing of exon 7 acts as a switch between these NLS types. Nuclear MBNL1 promotes nuclear retention of expanded CUG/CAG repeat RNA and represses expression of homopolymeric proteins produced by RAN translation. NLS mutagenesis, subcellular fractionation, immunofluorescence, alternative splicing analysis, reporter assays for RAN translation Human molecular genetics Medium 25274774
2014 Mbnl1 regulates alternative splicing during terminal erythropoiesis; knockdown blocks erythroid differentiation and disrupts developmentally regulated exon skipping of Ndel1 mRNA, which MBNL1 directly binds and which is critical for terminal erythroid proliferation. Mbnl1 knockdown in fetal liver erythroid progenitors, RIP, RT-PCR splicing assay, differentiation assay Blood Medium 24869935
2017 MBNL1 undergoes K63-linked polyubiquitination, which is required for its cytoplasmic localization and function in promoting neurite outgrowth. Expanded CUG RNA induces deubiquitination of cytoplasmic MBNL1, causing nuclear translocation and neurite morphology defects; inhibiting K63-linked polyubiquitin chain degradation ameliorates these defects. Ubiquitination assays (K63-specific), subcellular fractionation, immunofluorescence, neurite morphology assays, DM1 mouse brain analysis Cell reports Medium 29490267
2017 MBNL1 autoregulates its own protein levels through exon 1 exclusion: CLIP-seq shows MBNL1 binds its own exon 1 in pre-mRNA; MBNL proteins induce skipping of exon 1, which impacts polysome association and translation. Exon 1-deficient isoforms lacking the first two zinc fingers are highly unstable and have severely compromised splicing activity. CLIP-seq, RT-PCR, polysome profiling, EGFP fusion protein stability assays, splicing activity assays Nucleic acids research Medium 27903900
2018 MBNL1 exon 7 inclusion is required for MBNL1 protein homodimerization; components of the U2 splicing complex (SF3B1, SF3A1, PHF5A) are required for efficient exon 7 inclusion. Isoforms lacking exon 7 (MBNL1 Δex7) act as dominant-negative proteins that induce DNA damage and inhibit cell viability and migration. Splice-switching antisense oligonucleotides, siRNA, co-immunoprecipitation for homodimerization, cell viability and migration assays Life science alliance Medium 30456384
2018 rbFOX1 competes with MBNL1 for binding to expanded CCUG RNA repeats (but not CUG repeats). rbFOX1 overexpression partly releases MBNL1 from CCUG RNA foci in DM2 muscle cells and corrects alternative splicing alterations and muscle defects in a Drosophila DM2 model. RNA binding competition assays, immunofluorescence of foci, splicing assays, Drosophila genetic rescue Nature communications Medium 29789616
2015 MBNL1 overexpression increases nuclear retention of full-length expanded HTT (expHTT) RNA and decreases expHTT protein expression in the cytosol; U2AF65 has the opposite effect, decreasing expHTT nuclear retention. This indicates MBNL1 and U2AF65 regulate nuclear export of expHTT RNA. MBNL1/U2AF65 overexpression, subcellular fractionation, western blot, immunofluorescence Scientific reports Medium 26218986
2015 MBNL1 binds the terminal loop of C-allelic pre-miR-1307 via a UGCUGC motif, blocking Dicer recruitment and processing, resulting in downregulation of miR-1307 and subsequent upregulation of Bcl2. RNA pull-down, Dicer processing assays, luciferase reporter assay Carcinogenesis Medium 25977444
2017 Pseudouridine modification of YGCY motif-containing RNAs reduces MBNL1 binding by decreasing RNA flexibility, as revealed by molecular dynamics simulations. Modification of CCUG repeats causes only modest inhibition because not all pyrimidines in the YGCY motif can be modified. Fluorescence binding assays, molecular dynamics simulations The Journal of biological chemistry Medium 28130447
2019 TRIM71 represses MBNL1 through 3′ UTR hairpin-mediated target degradation, thereby promoting embryonic splicing patterns and stem cell states. TRIM71 mutations implicated in congenital hydrocephalus impair MBNL1 silencing. TRIM71 knockdown/overexpression, RNA-seq, RNA binding assays, mRNA stability assays Genes & development Medium 31371437
2020 MBNL1 loss-of-function in MLL-rearranged leukemia impairs leukemia propagation; MBNL1 regulates alternative splicing (predominantly intron exclusion) of DOT1L and SETD1A, genes essential for MLL-rearranged leukemogenesis. shRNA knockdown, RNA-seq, in vitro and in vivo leukemia propagation assays, small molecule MBNL1 inhibitor Nature communications Medium 32398749
2020 MBNL1 is essential for normal thymus development: Mbnl1 knockout mice develop postnatal thymic hyperplasia with thymocyte accumulation. Transcriptome analysis shows MBNL1 loss causes mis-splicing of TCF/LEF family transcription factors among many other RNA processing events. Mbnl1 knockout mice, RNA-seq, RT-PCR, histology Nature communications Medium 32332745
2020 In GBM stem cells under hypoxia, MBNL1 is exported from the nucleus, inhibiting its splicing activity and driving adult-to-fetal alternative splicing transitions that promote stem-like phenotypes. Forced expression of a constitutively active MBNL1 isoform inhibits GSC self-renewal and tumor growth in orthotopic transplantation models. Hypoxia cell culture, subcellular fractionation, immunofluorescence, orthotopic transplantation, survival analysis Cancer research Medium 32928918
2020 MBNL1 overexpression inhibits autophagy via the mTOR pathway to reverse the proliferation defect of DM1 skeletal muscle satellite cells (SSCs). Rapamycin treatment abolished the proliferative benefit of MBNL1 overexpression, placing MBNL1 upstream of mTOR in SSC autophagy regulation. iPSC-derived SSCs, MBNL1 overexpression, rapamycin treatment, autophagy assays, mTOR phosphorylation western blot Cell death & disease Medium 32683410
2020 MBNL1 downregulation in cancer leads to a MAP2K7Δexon2 splice variant that activates JNK signaling, driving tumor dedifferentiation and stem/progenitor-like properties. JNK inhibition reverses MAP2K7Δexon2-driven dedifferentiation in MBNL1-low cancer cells, placing MBNL1 upstream of MAP2K7/JNK in cancer differentiation. RNA-seq, MBNL1 knockdown/overexpression, splicing reporter assays, JNK inhibitor epistasis, in vitro and in vivo tumor models Proceedings of the National Academy of Sciences of the United States of America Medium 32601196
2021 Loss of MBNL1 in VSMC induces Abi1-Δe10 splice isoform expression; Abi1-Δe10 constitutively activates Rac1 independent of upstream stimulation, triggering the Rac1-NOX1-ROS pathway and increasing KLF4 transcription factor expression, promoting VSMC macrophage-like transdifferentiation during atherogenesis. RT-PCR splicing assays, MBNL1 knockdown, Rac1 activation assays, ROS measurement, VSMC transdifferentiation assays, patient tissue analysis Cell proliferation Medium 33759281
2022 MBNL1 regulates cardiomyocyte maturation and the postnatal switch from hyperplastic to hypertrophic growth. MBNL1 is regulated by the MEIS1/calcineurin signaling axis. Loss of MBNL1 increases cardiomyocyte cell cycle entry through altered cell cycle inhibitor transcript stability; MBNL1-dependent stabilization of estrogen-related receptor signaling maintains cardiomyocyte maturity. MBNL1 dosage controls the temporal window of neonatal cardiac regeneration. Gain- and loss-of-function mouse models, multi-omics, biochemical and histological assays, neonatal cardiac regeneration models Circulation High 38426339
2022 Complete ablation of both MBNL1 and MBNL2 in cardiomyocytes (Myh6-Cre double KO) causes spontaneous lethal cardiac arrhythmia. RNA-seq recapitulates DM spliceopathy; Calsequestrin 1 is upregulated ~6-fold and EGF protein is reduced ~50%, revealing potential mechanisms for DM cardiac pathogenesis. Cardiomyocyte-specific double knockout mice, RNA-seq, immunoblotting, cardiac electrophysiology Human molecular genetics Medium 35567413
2022 MBNL1 drives fibroblast-to-myofibroblast state transitions and controls fibroblast state plasticity during cardiac wound healing. Fibroblast-specific MBNL1 overexpression transitions fibroblasts to myofibroblast transcriptome and promotes scar maturation; loss of MBNL1 in fibroblasts or myofibroblasts limits scar production. MBNL1 deletion combined with injury caused quiescent fibroblasts to expand and adopt cardiac mesenchymal stem cell features. Fibroblast/myofibroblast-specific gain- and loss-of-function mouse models, cardiac injury models, transcriptomic profiling Cell stem cell High 35176223
2023 MBNL1 loss upregulates its paralog MBNL2 through a splicing-based compensation mechanism: loss of MBNL1 increases inclusion of Mbnl2 exon 9, which eliminates a C-terminal PEST domain that normally targets MBNL2 for proteasomal degradation, thereby stabilizing MBNL2. Additionally, increased Mbnl2 exon 6 inclusion shifts MBNL2 to the nucleus. RT-PCR, MBNL1 knockout mouse tissues, protein stability assays, MBNL2 localization assays Nucleic acids research Medium 36617982

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Failure of MBNL1-dependent post-natal splicing transitions in myotonic dystrophy. Human molecular genetics 427 16717059
2004 MBNL1 is the primary determinant of focus formation and aberrant insulin receptor splicing in DM1. The Journal of biological chemistry 166 15546872
2012 CUGBP1 and MBNL1 preferentially bind to 3' UTRs and facilitate mRNA decay. Scientific reports 151 22355723
2008 Dynamic combinatorial selection of molecules capable of inhibiting the (CUG) repeat RNA-MBNL1 interaction in vitro: discovery of lead compounds targeting myotonic dystrophy (DM1). Journal of the American Chemical Society 145 18998634
2004 Muscleblind protein, MBNL1/EXP, binds specifically to CHHG repeats. Human molecular genetics 141 14722159
2008 Structural insights into RNA recognition by the alternative-splicing regulator muscleblind-like MBNL1. Nature structural & molecular biology 139 19043415
1988 Cloning of a chromosomal locus (exp) which regulates the expression of several exoprotein genes in Staphylococcus aureus. Molecular & general genetics : MGG 136 3285138
2003 EXP-1 is an excitatory GABA-gated cation channel. Nature neuroscience 132 14555952
2010 MBNL1 binds GC motifs embedded in pyrimidines to regulate alternative splicing. Nucleic acids research 122 20071745
2009 The protein factors MBNL1 and U2AF65 bind alternative RNA structures to regulate splicing. Proceedings of the National Academy of Sciences of the United States of America 118 19470458
2006 MBNL1 and CUGBP1 modify expanded CUG-induced toxicity in a Drosophila model of myotonic dystrophy type 1. Human molecular genetics 116 16723374
2013 MBNL1 and RBFOX2 cooperate to establish a splicing programme involved in pluripotent stem cell differentiation. Nature communications 110 24048253
2003 Developmental expression of mouse muscleblind genes Mbnl1, Mbnl2 and Mbnl3. Gene expression patterns : GEP 105 12915312
1997 The 32-kilobase exp gene cluster of Rhizobium meliloti directing the biosynthesis of galactoglucan: genetic organization and properties of the encoded gene products. Journal of bacteriology 104 9023225
2018 The Hairpin Form of r(G4C2)exp in c9ALS/FTD Is Repeat-Associated Non-ATG Translated and a Target for Bioactive Small Molecules. Cell chemical biology 92 30503283
2012 A small molecule that targets r(CGG)(exp) and improves defects in fragile X-associated tremor ataxia syndrome. ACS chemical biology 91 22948243
2000 Active transport of the angiotensin-II antagonist losartan and its main metabolite EXP 3174 across MDCK-MDR1 and caco-2 cell monolayers. British journal of pharmacology 88 10725273
2015 MBNL1-mediated regulation of differentiation RNAs promotes myofibroblast transformation and the fibrotic response. Nature communications 77 26670661
2011 New function for the RNA helicase p68/DDX5 as a modifier of MBNL1 activity on expanded CUG repeats. Nucleic acids research 66 22156369
2011 Autoregulated splicing of muscleblind-like 1 (MBNL1) Pre-mRNA. The Journal of biological chemistry 64 21832083
2010 Muscleblind-like 1 (Mbnl1) promotes insulin receptor exon 11 inclusion via binding to a downstream evolutionarily conserved intronic enhancer. The Journal of biological chemistry 64 20519504
2006 Organization of ETRAMPs and EXP-1 at the parasite-host cell interface of malaria parasites. Molecular microbiology 64 16420351
2008 MBNL1 associates with YB-1 in cytoplasmic stress granules. Journal of neuroscience research 62 18335541
2020 Metformin Reduces the Senescence of Renal Tubular Epithelial Cells in Diabetic Nephropathy via the MBNL1/miR-130a-3p/STAT3 Pathway. Oxidative medicine and cellular longevity 61 32104542
2018 rbFOX1/MBNL1 competition for CCUG RNA repeats binding contributes to myotonic dystrophy type 1/type 2 differences. Nature communications 61 29789616
2014 Nuclear localization of MBNL1: splicing-mediated autoregulation and repression of repeat-derived aberrant proteins. Human molecular genetics 59 25274774
2018 Alternative splicing analysis in human monocytes and macrophages reveals MBNL1 as major regulator. Nucleic acids research 57 29771377
2022 MBNL1 drives dynamic transitions between fibroblasts and myofibroblasts in cardiac wound healing. Cell stem cell 56 35176223
2020 MBNL1 regulates essential alternative RNA splicing patterns in MLL-rearranged leukemia. Nature communications 54 32398749
2014 Lomofungin and dilomofungin: inhibitors of MBNL1-CUG RNA binding with distinct cellular effects. Nucleic acids research 53 24799433
2013 A novel CUG(exp)·MBNL1 inhibitor with therapeutic potential for myotonic dystrophy type 1. ACS chemical biology 52 23480597
1999 A mutation in the C. elegans EXP-2 potassium channel that alters feeding behavior. Science (New York, N.Y.) 51 10617464
2011 Mis-splicing of Tau exon 10 in myotonic dystrophy type 1 is reproduced by overexpression of CELF2 but not by MBNL1 silencing. Biochimica et biophysica acta 50 21439371
2007 Overexpression of MBNL1 fetal isoforms and modified splicing of Tau in the DM1 brain: two individual consequences of CUG trinucleotide repeats. Experimental neurology 49 18177861
2014 Muscleblind-like 1 (Mbnl1) regulates pre-mRNA alternative splicing during terminal erythropoiesis. Blood 48 24869935
2018 MBNL1 alternative splicing isoforms play opposing roles in cancer. Life science alliance 47 30456384
2017 Pseudouridine Modification Inhibits Muscleblind-like 1 (MBNL1) Binding to CCUG Repeats and Minimally Structured RNA through Reduced RNA Flexibility. The Journal of biological chemistry 47 28130447
2014 RBFOX1 cooperates with MBNL1 to control splicing in muscle, including events altered in myotonic dystrophy type 1. PloS one 47 25211016
2015 Nuclear retention of full-length HTT RNA is mediated by splicing factors MBNL1 and U2AF65. Scientific reports 44 26218986
2016 Small Molecule Recognition and Tools to Study Modulation of r(CGG)(exp) in Fragile X-Associated Tremor Ataxia Syndrome. ACS chemical biology 42 27276216
2010 Identification of MBNL1 and MBNL3 domains required for splicing activation and repression. Nucleic acids research 42 21109529
1997 Angiotensin II receptor antagonist EXP 3174 reduces infarct size comparable with enalaprilat and augments preconditioning in the pig heart. Cardiovascular drugs and therapy 42 9493708
2020 MBNL1 reverses the proliferation defect of skeletal muscle satellite cells in myotonic dystrophy type 1 by inhibiting autophagy via the mTOR pathway. Cell death & disease 41 32683410
2018 Ubiquitination of MBNL1 Is Required for Its Cytoplasmic Localization and Function in Promoting Neurite Outgrowth. Cell reports 40 29490267
2015 The polymorphic terminal-loop of pre-miR-1307 binding with MBNL1 contributes to colorectal carcinogenesis via interference with Dicer1 recruitment. Carcinogenesis 40 25977444
2017 Seasonal variations of U.S. mortality rates: Roles of solar ultraviolet-B doses, vitamin D, gene exp ression, and infections. The Journal of steroid biochemistry and molecular biology 39 28088363
2019 Long non-coding RNA MBNL1-AS1 regulates proliferation, migration, and invasion of cancer stem cells in colon cancer by interacting with MYL9 via sponging microRNA-412-3p. Clinics and research in hepatology and gastroenterology 38 31255531
2017 Autoregulation of MBNL1 function by exon 1 exclusion from MBNL1 transcript. Nucleic acids research 38 27903900
2016 Phenylbutazone induces expression of MBNL1 and suppresses formation of MBNL1-CUG RNA foci in a mouse model of myotonic dystrophy. Scientific reports 38 27126921
1993 Central administration of PD 123319 or EXP-3174 inhibits effects of angiotensin II. The American journal of physiology 38 7679256
1992 Inhibition of the haemodynamic effects of angiotensin II in conscious rats by AT2-receptor antagonists given after the AT1-receptor antagonist, EXP 3174. British journal of pharmacology 37 1472980
2019 microRNA-301b-3p downregulation underlies a novel inhibitory role of long non-coding RNA MBNL1-AS1 in non-small cell lung cancer. Stem cell research & therapy 36 31113460
2013 MBNL1 and PTB cooperate to repress splicing of Tpm1 exon 3. Nucleic acids research 36 23511971
2010 Effects of myricetin, an antioxidant, on the pharmacokinetics of losartan and its active metabolite, EXP-3174, in rats: possible role of cytochrome P450 3A4, cytochrome P450 2C9 and P-glycoprotein inhibition by myricetin. The Journal of pharmacy and pharmacology 36 20636879
2020 A tumor-associated splice-isoform of MAP2K7 drives dedifferentiation in MBNL1-low cancers via JNK activation. Proceedings of the National Academy of Sciences of the United States of America 35 32601196
2019 The RNA hairpin binder TRIM71 modulates alternative splicing by repressing MBNL1. Genes & development 35 31371437
2017 Plasmodium berghei EXP-1 interacts with host Apolipoprotein H during Plasmodium liver-stage development. Proceedings of the National Academy of Sciences of the United States of America 35 28137845
2011 Selective inhibition of MBNL1-CCUG interaction by small molecules toward potential therapeutic agents for myotonic dystrophy type 2 (DM2). Nucleic acids research 35 21768123
2011 The four Zn fingers of MBNL1 provide a flexible platform for recognition of its RNA binding elements. BMC molecular biology 34 21548961
2012 RNA splicing is responsive to MBNL1 dose. PloS one 32 23166594
2011 MBNL1-RNA recognition: contributions of MBNL1 sequence and RNA conformation. Chembiochem : a European journal of chemical biology 32 22106026
2019 LncRNA MBNL1-AS1 represses cell proliferation and enhances cell apoptosis via targeting miR-135a-5p/PHLPP2/FOXO1 axis in bladder cancer. Cancer medicine 30 31769229
2017 Reduced cytoplasmic MBNL1 is an early event in a brain-specific mouse model of myotonic dystrophy. Human molecular genetics 30 28369378
2017 A flow cytometry-based screen identifies MBNL1 modulators that rescue splicing defects in myotonic dystrophy type I. Human molecular genetics 30 28535287
2013 Single-molecule study of the CUG repeat-MBNL1 interaction and its inhibition by small molecules. Nucleic acids research 29 23661680
2022 LncRNA MBNL1-AS1 represses gastric cancer progression via the TGF-β pathway by modulating miR-424-5p/Smad7 axis. Bioengineered 28 35311623
2022 The MBNL1/circNTRK2/PAX5 pathway regulates aerobic glycolysis in glioblastoma cells by encoding a novel protein NTRK2-243aa. Cell death & disease 28 36064939
2022 STAT3/miR-130b-3p/MBNL1 feedback loop regulated by mTORC1 signaling promotes angiogenesis and tumor growth. Journal of experimental & clinical cancer research : CR 28 36217202
2020 The Alternative Splicing Factor, MBNL1, Inhibits Glioblastoma Tumor Initiation and Progression by Reducing Hypoxia-Induced Stemness. Cancer research 28 32928918
2019 Piperine Modulates Protein Mediated Toxicity in Fragile X-Associated Tremor/Ataxia Syndrome through Interacting Expanded CGG Repeat (r(CGG)exp) RNA. ACS chemical neuroscience 28 31264835
1998 Characterization and cloning of the gene encoding the vacuolar membrane protein EXP-2 from Plasmodium falciparum. Molecular and biochemical parasitology 28 9574909
2014 Tau exon 2 responsive elements deregulated in myotonic dystrophy type I are proximal to exon 2 and synergistically regulated by MBNL1 and MBNL2. Biochimica et biophysica acta 26 24440524
2009 RNA/MBNL1-containing foci in myoblast nuclei from patients affected by myotonic dystrophy type 2: an immunocytochemical study. European journal of histochemistry : EJH 26 19864209
2017 Interplay of classic Exp and specific Vfm quorum sensing systems on the phenotypic features of Dickeya solani strains exhibiting different virulence levels. Molecular plant pathology 24 28921772
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2009 Ribonuclear inclusions and MBNL1 nuclear sequestration do not affect myoblast differentiation but alter gene splicing in myotonic dystrophy type 2. Neuromuscular disorders : NMD 24 19345584
2019 The interaction between 30b-5p miRNA and MBNL1 mRNA is involved in vascular smooth muscle cell differentiation in patients with coronary atherosclerosis. International journal of molecular sciences 23 31861407
2024 A Simple and Robust Exponential Amplification Reaction (EXPAR)-Based Hairpin Template (exp-Hairpin) for Highly Specific, Sensitive, and Universal MicroRNA Detection. Analytical chemistry 22 38295438
2020 MiR-362-5p, Which Is Regulated by Long Non-Coding RNA MBNL1-AS1, Promotes the Cell Proliferation and Tumor Growth of Bladder Cancer by Targeting QKI. Frontiers in pharmacology 22 32194406
2020 Loss of MBNL1 induces RNA misprocessing in the thymus and peripheral blood. Nature communications 21 32332745
2023 Transcriptome-Wide Studies of RNA-Targeted Small Molecules Provide a Simple and Selective r(CUG)exp Degrader in Myotonic Dystrophy. ACS central science 20 37521782
2022 A blood-brain penetrant RNA-targeted small molecule triggers elimination of r(G4C2)exp in c9ALS/FTD via the nuclear RNA exosome. Proceedings of the National Academy of Sciences of the United States of America 20 36409902
2021 RNA Splicing of the Abi1 Gene by MBNL1 contributes to macrophage-like phenotype modulation of vascular smooth muscle cell during atherogenesis. Cell proliferation 20 33759281
2020 Down-regulation of MBNL1-AS1 contributes to tumorigenesis of NSCLC via sponging miR-135a-5p. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 20 32092823
2022 The Regulatory Role of Both MBNL1 and MBNL1-AS1 in Several Common Cancers. Current pharmaceutical design 19 34459372
2020 Curcumin Regulates the r(CGG)exp RNA Hairpin Structure and Ameliorate Defects in Fragile X-Associated Tremor Ataxia Syndrome. Frontiers in neuroscience 19 32317919
2012 Combinatorial mutagenesis of MBNL1 zinc fingers elucidates distinct classes of regulatory events. Molecular and cellular biology 19 22890842
2022 The mechanism of BUD13 m6A methylation mediated MBNL1-phosphorylation by CDK12 regulating the vasculogenic mimicry in glioblastoma cells. Cell death & disease 18 36463205
2019 MBNL1 overexpression is not sufficient to rescue the phenotypes in a mouse model of RNA toxicity. Human molecular genetics 18 30997488
2019 (CTG)n repeat-mediated dysregulation of MBNL1 and MBNL2 expression during myogenesis in DM1 occurs already at the myoblast stage. PloS one 18 31116797
2018 Opposing roles of miR-294 and MBNL1/2 in shaping the gene regulatory network of embryonic stem cells. EMBO reports 18 29735517
2008 A putative role of ribonuclear inclusions and MBNL1 in the impairment of gallbladder smooth muscle contractility with cholelithiasis in myotonic dystrophy type 1. Neuromuscular disorders : NMD 18 18653337
2005 Calcineurin regulates enteric muscle contraction through EXP-1, excitatory GABA-gated channel, in C. elegans. Journal of molecular biology 18 16084527
2022 Tumour-suppressing functions of the lncRNA MBNL1-AS1/miR-889-3p/KLF9 axis in human breast cancer cells. Cell cycle (Georgetown, Tex.) 17 35112997
2018 Downregulation of the long noncoding RNA MBNL1-AS1 protects sevoflurane-pretreated mice against ischemia-reperfusion injury by targeting KCNMA1. Experimental & molecular medicine 17 30185781
2024 MBNL1 Regulates Programmed Postnatal Switching Between Regenerative and Differentiated Cardiac States. Circulation 16 38426339
2023 Alternative splicing mediates the compensatory upregulation of MBNL2 upon MBNL1 loss-of-function. Nucleic acids research 16 36617982
2018 Daunorubicin reduces MBNL1 sequestration caused by CUG-repeat expansion and rescues cardiac dysfunctions in a Drosophila model of myotonic dystrophy. Disease models & mechanisms 16 29592894
1996 Angiotensin type 1 receptor antagonists CV-11974 and EXP 3174 cause selective renal vasodilatation in conscious spontaneously hypertensive rats. Clinical science (London, England : 1979) 16 8795437
2022 Mice lacking MBNL1 and MBNL2 exhibit sudden cardiac death and molecular signatures recapitulating myotonic dystrophy. Human molecular genetics 15 35567413