Affinage

RBM46

Probable RNA-binding protein 46 · UniProt Q8TBY0

Length
533 aa
Mass
60.0 kDa
Annotated
2026-06-10
11 papers in source corpus 10 papers cited in narrative 10 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RBM46 is a germ cell-enriched, cytoplasmic RNA-binding protein that governs the mitotic-to-meiotic transition during gametogenesis by acting as a sequence-specific posttranscriptional regulator within the YTHDC2/MEIOC complex (PMID:36001654, PMID:36129965). In the testis it assembles with YTHDC2 and MEIOC, binding U-rich consensus motifs in the 3' UTRs of mitotic transcripts near YTHDC2 sites to target them for degradation, thereby down-regulating the mitotic program at meiotic entry (PMID:36001654). RBM46 also recognizes GCCUAU/GUUCGA motifs in the 3' UTRs of meiotic cohesin subunit mRNAs and, rather than altering their abundance, promotes their translation; loss of RBM46 impairs axial element assembly and causes synaptic failure and meiotic arrest (PMID:36726756). Rbm46-null mice are infertile with testes depleted of differentiating germ cells, establishing an essential role in spermatogonial differentiation and meiotic initiation (PMID:36129965), and the same RBM46/MEIOC/YTHDC2 module drives meiotic initiation in oogenesis by repressing transcripts such as Lin28a and Mga through defined 3'UTR binding motifs (PMID:42217413). Beyond germline meiosis, RBM46 controls early embryonic lineage specification by post-transcriptionally regulating β-Catenin and Cdx2 mRNAs to direct trophectoderm versus endoderm fate (PMID:28212427, PMID:25397698), supports embryonic stem cell self-renewal through regulation of Bnip3-mediated mitophagy (PMID:38518724), and serves as a cofactor for APOBEC1-mediated C-to-U RNA editing (PMID:38708190).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2014 Medium

    Established RBM46 as a sequence-specific mRNA-binding protein with a developmental output by showing it directly binds and stabilizes a fate-determining transcript in early embryos.

    Evidence RNA immunoprecipitation and RNAi knockdown in mouse embryos with trophectoderm marker analysis

    PMID:25397698

    Open questions at the time
    • Mechanism of mRNA stabilization not defined
    • No binding motif mapped at this stage
    • Single-lab finding
  2. 2017 Medium

    Extended RBM46 function to stem cell fate by showing it acts in the cytoplasm to destabilize a specific signaling transcript, controlling differentiation direction.

    Evidence Subcellular fractionation, gain/loss-of-function in mESCs, and mRNA stability assays for β-Catenin

    PMID:28212427

    Open questions at the time
    • Direct binding site on β-Catenin mRNA not mapped
    • Degradation machinery not identified
    • Single lab
  3. 2021 Medium

    Defined RBM46 as a germ cell-specific posttranscriptional regulator required for spermatogenesis and meiosis using an ortholog loss-of-function model.

    Evidence TALEN rbm46 mutant zebrafish with in situ hybridization and RNA-seq of germ cell genes

    PMID:33524105

    Open questions at the time
    • Direct targets not validated by binding assays
    • No complex partners identified
    • Translation vs decay mechanism unresolved
  4. 2022 High

    Placed RBM46 mechanistically at the mitotic-to-meiotic switch by identifying it as a component of the YTHDC2/MEIOC complex that targets mitotic transcripts for degradation, and mapping its U-rich binding consensus genome-wide.

    Evidence Testis-specific Rbm46 KO mice, Co-IP complex identification, target degradation assays, and eCLIP-seq with localization in mouse germ cells

    PMID:36001654 PMID:36129965

    Open questions at the time
    • Structural basis of complex assembly not defined
    • Recruitment hierarchy among RBM46/YTHDC2/MEIOC unresolved
    • Degradation effector machinery not fully mapped
  5. 2022 High

    Revealed a dual regulatory mode: beyond promoting decay, RBM46 binds GCCUAU/GUUCGA motifs to enhance translation of meiotic cohesin mRNAs without changing their levels, explaining synaptonemal complex failure on its loss.

    Evidence LACE-seq single-nucleotide binding profiling, Rbm46 KO mice, polysome/translation assays, and synaptonemal complex immunofluorescence

    PMID:36726756

    Open questions at the time
    • Molecular basis for switch between decay and translational promotion unknown
    • Translation machinery engaged not identified
    • How motif context dictates outcome unresolved
  6. 2023 Medium

    Broadened RBM46 biochemical activity by identifying it as a cofactor that enables APOBEC1-mediated C-to-U RNA editing.

    Evidence Biochemical cofactor identification and in vitro RNA editing activity assays with circular RNA sequencing for target identification

    PMID:38708190

    Open questions at the time
    • In vivo relevance of editosome activity not established
    • Relationship to YTHDC2/MEIOC function unclear
    • Single lab, single paper
  7. 2024 Medium

    Linked RBM46 to ESC homeostasis by showing it regulates a mitophagy transcript, connecting its RNA control to redox balance and self-renewal.

    Evidence Rbm46 KO in ESCs with ROS measurement, mitophagy assays, and Bnip3 mRNA analysis

    PMID:38518724

    Open questions at the time
    • Direct binding to Bnip3 mRNA not demonstrated
    • Decay vs translation mode not specified
    • Single lab
  8. 2026 Medium

    Generalized RBM46's meiotic role to the female germline and confirmed motif-dependent repression by reconstituting the RBM46/MEIOC/YTHDC2 module on defined 3'UTR targets.

    Evidence Rbm46 KO ovary phenotyping, transcriptomics, and reporter mRNA decay assays in HEK293T with binding-motif deletion

    PMID:42217413

    Open questions at the time
    • Endogenous Lin28a/Mga regulation not validated beyond reporters
    • Stoichiometry of reconstituted complex unknown
    • Single lab
  9. 2026 Medium

    Positioned rbm46 within an upstream epigenetic regulatory circuit by showing a histone demethylase controls its promoter chromatin state and that rbm46 acts downstream in metabolic homeostasis.

    Evidence kdm4aa KO zebrafish with CUT&Tag-qPCR for promoter histone marks and rbm46 mRNA rescue of ROS/ATP phenotypes

    PMID:41797481

    Open questions at the time
    • Direct vs indirect chromatin control of rbm46 promoter unresolved
    • Mammalian conservation of this axis untested
    • Mechanism linking rbm46 to ATP/ROS not detailed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How RBM46 mechanistically switches between promoting mRNA decay and enhancing translation, and the structural basis for its assembly into the YTHDC2/MEIOC complex versus the APOBEC1 editosome, remain unresolved.
  • No structural model of RBM46 in any complex
  • Determinants selecting decay vs translation output unknown
  • Integration of germline meiotic and somatic ESC functions unexplained

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 5 GO:0048018 receptor ligand activity 1
Localization
GO:0005829 cytosol 2
Pathway
R-HSA-1474165 Reproduction 4 R-HSA-8953854 Metabolism of RNA 3 R-HSA-1266738 Developmental Biology 2
Partners
APOBEC1MEIOCYTHDC2
Complex memberships
APOBEC1 editosomeYTHDC2/MEIOC complex

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2022 RBM46 is a component of the YTHDC2/MEIOC complex in mouse testes. RBM46 binds to the 3' UTR of mitotic transcripts within 100 nucleotides from YTHDC2 U-rich motifs and targets these transcripts for degradation, establishing the RBM46/YTHDC2/MEIOC complex as the major posttranscriptional regulator responsible for down-regulating mitotic transcripts during meiosis entry in spermatogenesis. Testis-specific Rbm46 knockout mice, Co-immunoprecipitation/complex identification, RNA binding and target degradation assays Science advances High 36001654
2022 RBM46 binds via a U-rich conserved consensus sequence to mRNAs encoding proteins required for spermatogonial differentiation and meiotic initiation, as determined by eCLIP-seq in mice. RBM46 localizes to the cytoplasm of premeiotic spermatogonia and meiotic spermatocytes. Rbm46 knockout mice are infertile, with testes containing only Sertoli cells and few undifferentiated spermatogonia, establishing an essential role in spermatogonial differentiation. Rbm46 knockout mice, eCLIP-seq, RNA-seq, subcellular localization by immunofluorescence PLoS genetics High 36129965
2022 RBM46 preferentially binds target mRNAs containing GCCUAU/GUUCGA motifs in their 3' UTRs of mRNAs encoding multiple meiotic cohesin subunits (as determined by LACE-seq at single-nucleotide resolution). In Rbm46 knockout mice, RBM46-target cohesin subunits display unaltered mRNA levels but reduced translation, resulting in failed assembly of axial elements, synapsis disruption, and meiotic arrest. LACE-seq, Rbm46 knockout mice, polysome/translation assays, synaptonemal complex immunofluorescence Protein & cell High 36726756
2021 In zebrafish, rbm46 is specifically expressed in germ cells. rbm46 mutants display impaired spermatogenesis with meiosis not observed, and RNA-seq indicated Rbm46 is involved in posttranscriptional regulation of germ cell development genes including nanos3, dazl, and sycp3. TALEN-generated rbm46 mutant zebrafish, in situ hybridization, RT-PCR, RNA-seq Biology of reproduction Medium 33524105
2017 RBM46 localizes primarily to the cytoplasm of mouse embryonic stem cells (mESCs) and is elevated during ESC differentiation. RBM46 regulates the degradation of β-Catenin mRNA post-transcriptionally. Overexpression of Rbm46 drives mESC differentiation into trophectoderm, while knockdown leads to endoderm differentiation. Subcellular fractionation/immunofluorescence, overexpression and knockdown in mESCs, mRNA stability assays PloS one Medium 28212427
2014 RBM46 directly binds to and stabilizes Cdx2 mRNA in early mouse embryos. Knockdown of Rbm46 downregulates trophectoderm markers and blocks allocation of blastomere cells to the trophectoderm. RNA immunoprecipitation, RNAi knockdown in mouse embryos, marker expression analysis Stem cells and development Medium 25397698
2023 RBM46 was identified as a novel cofactor for APOBEC1 (A1), facilitating A1-mediated C-to-U RNA editing on ApoB mRNA and other cellular RNA targets. The A1/RBM46 complex functions as an editosome. Biochemical cofactor identification, in vitro RNA editing activity assay, circular RNA sequencing (low-error) for target identification Journal of molecular biology Medium 38708190
2024 RBM46 acts as a direct post-transcriptional regulator of Bnip3 mRNA expression in mouse ESCs. Rbm46 knockout leads to diminished mitophagy (BNIP3-mediated) and elevated reactive oxygen species, disrupting ESC self-renewal. Rbm46 knockout in ESCs, ROS measurement, mitophagy assays, mRNA expression analysis Biochemical and biophysical research communications Medium 38518724
2026 RBM46 promotes meiotic initiation during oogenesis. RBM46 deficiency leads to derepression of CCNA2, meiotic arrest at leptotene stage, and germ cell apoptosis in embryonic ovaries with upregulation of Stra8 and Lin28a and downregulation of meiotic genes. In HEK293T cells, ectopic co-expression of RBM46, MEIOC, and YTHDC2 promoted degradation of reporter mRNAs bearing Lin28a or Mga 3'UTRs; deletion of the RBM46-binding motif 'AAUCAU' within Lin28a 3'UTR reduced this repressive effect. Rbm46 knockout mice (ovary phenotype), transcriptomic profiling, reporter mRNA decay assays in HEK293T with motif deletion Biochemical and biophysical research communications Medium 42217413
2026 In zebrafish, kdm4aa knockout suppresses rbm46 mRNA expression via epigenetic mechanisms (decreased H3K4me3, increased H3K9me3 and H3K36me3 at the rbm46 promoter). Injection of rbm46 mRNA rescued elevated ROS and reduced ATP in kdm4aa-/- embryos, placing rbm46 downstream of kdm4aa in embryogenesis. kdm4aa knockout zebrafish, CUT&Tag-qPCR for histone marks at rbm46 promoter, rbm46 mRNA rescue injection, ROS and ATP measurement Zygote (Cambridge, England) Medium 41797481

Source papers

Stage 0 corpus · 11 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2022 RNA binding protein RBM46 regulates mitotic-to-meiotic transition in spermatogenesis. Science advances 33 36001654
2022 The germ cell-specific RNA binding protein RBM46 is essential for spermatogonial differentiation in mice. PLoS genetics 19 36129965
2021 Rbm46, a novel germ cell-specific factor, modulates meiotic progression and spermatogenesis. Biology of reproduction 16 33524105
2022 RBM46 is essential for gametogenesis and functions in post-transcriptional roles affecting meiotic cohesin subunits. Protein & cell 11 36726756
2017 Rbm46 regulates mouse embryonic stem cell differentiation by targeting β-Catenin mRNA for degradation. PloS one 9 28212427
2014 Rbm46 regulates trophectoderm differentiation by stabilizing Cdx2 mRNA in early mouse embryos. Stem cells and development 8 25397698
2023 Identification of RBM46 as a novel APOBEC1 cofactor for C-to-U RNA-editing activity. Journal of molecular biology 4 38708190
2024 Rbm46 inhibits reactive oxygen species in mouse embryonic stem cells through modulating BNIP3-mediated mitophagy. Biochemical and biophysical research communications 2 38518724
2026 kdm4aa knockout disturbs early embryonic development in Zebrafish via downregulating rbm46. Zygote (Cambridge, England) 0 41797481
2026 Methylation and Expression Analysis of POU4F2, HOXA9, RBM46, and TSGA10 Genes in Bladder Cancer Using Methyl-Sensitive Restriction Enzyme PCR (MSRE-PCR). Cancer management and research 0 41836594
2026 RBM46 promotes meiotic initiation during oogenesis. Biochemical and biophysical research communications 0 42217413

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