METTL23

METTL23 is an S-adenosyl-methionine-dependent protein arginine methyltransferase that catalyzes asymmetric dimethylation of histone H3 at arginine 17 (H3R17me2a) and thereby couples a chromatin mark to transcriptional and epigenetic programs in distinct cell types (PMID:28930672, PMID:36099048). Its enzymatic activity toward H3R17 was demonstrated by in vitro methyltransferase assay with recombinant protein and confirmed by pharmacological inhibition in zygotes (PMID:28930672). In the mouse zygote, maternal METTL23-generated H3R17me2a recruits the GSE–Tet3 5mC-oxidizing complex to the paternal genome, with which METTL23 physically associates, enabling 5hmC accumulation and active DNA demethylation of the male pronucleus (PMID:28930672). In retinal ganglion cells, METTL23-dependent H3R17me2a drives transcription of the estrogen-receptor-α target gene pS2, and its loss de-represses NF-κB-mediated TNF-α/IL-1β signaling and causes RGC death, as established in knock-in and knockout mouse models (PMID:36099048). Independently of histone methylation, METTL23 acts as a transcriptional co-regulator by physically binding the GABPA transcription factor to modulate downstream target genes such as THPO and ATP5B (PMID:24501276). METTL23 is not the methyltransferase responsible for eEF1A lysine methylation (PMID:28663172).

1. 2014 Medium

   Established that METTL23 functions in transcription by physically partnering with a defined transcription factor rather than acting in isolation, framing it as a GABPA co-regulator.

   Evidence Co-IP with GABPA, THPO promoter reporter, and siRNA knockdown with RT-PCR of ATP5B in human cells

   PMID:24501276

   Open questions at the time

   • Whether transcriptional co-regulation depends on methyltransferase activity was not tested
   • No catalytic substrate identified in this context
2. 2014 Low

   Linked truncating METTL23 mutations to disruption of the predicted SAM-dependent catalytic domain and altered localization, implicating loss of enzymatic function.

   Evidence 3D modelling of mutant protein, localization assay of truncated vs wild-type protein, co-expression analysis

   PMID:24626631

   Open questions at the time

   • Heat shock protein substrate association is correlative with no direct methylation assay
   • Catalytic activity inferred from modelling only
3. 2017 Medium

   Resolved METTL23's catalytic identity by showing it is a protein arginine methyltransferase that generates H3R17me2a, defining its substrate and mark.

   Evidence In vitro methyltransferase assay with recombinant Mettl23, TBBD inhibitor treatment, and H3R17me2a immunofluorescence in mouse zygotes

   PMID:28930672

   Open questions at the time

   • Single lab; structural basis of arginine recognition not determined
   • Whether other arginine substrates exist not addressed
4. 2017 Medium

   Connected the H3R17me2a mark to a downstream epigenetic outcome by showing METTL23 recruits the GSE–Tet3 complex for paternal genome demethylation.

   Evidence Co-IP of Mettl23–Tet3–GSE, oocyte depletion (RNAi/morpholino), and immunofluorescence for GSE, Tet3, and 5hmC in the male pronucleus

   PMID:28930672

   Open questions at the time

   • Direct demonstration that H3R17me2a is the recruiting mark vs scaffolding role not separated
   • Single lab
5. 2017 Medium

   Excluded eEF1A as a METTL23 substrate, sharpening its substrate specificity to histone arginine rather than non-histone lysine methylation.

   Evidence CRISPR/Cas9 knockout in K562 cells with targeted mass spectrometry of eEF1A methylation

   PMID:28663172

   Open questions at the time

   • Negative result for one substrate does not enumerate the full substrate range
6. 2022 High

   Demonstrated a physiological consequence of METTL23 catalysis in vivo: H3R17me2a drives pS2 transcription to restrain neuroinflammation and protect retinal ganglion cells.

   Evidence Mettl23 knock-in and knockout mice, in vitro methyltransferase assay, H3R17me2a immunofluorescence, and pS2/TNF-α/IL-1β expression analysis

   PMID:36099048

   Open questions at the time

   • Mechanism linking pS2 to NF-κB suppression not fully resolved
   • Whether GABPA co-regulation contributes in retina not tested
7. 2026 Low

   Implicated METTL23 in a host–virus context through a nuclear interaction with JMJD6 during pseudorabies virus infection.

   Evidence Nuclear co-immunoprecipitation of METTL23 with JMJD6 during PRV infection

   PMID:42053297

   Open questions at the time

   • Single Co-IP without reciprocal validation
   • No functional dissection of METTL23's role in immune evasion
   • Catalytic relevance of the interaction unknown

• How METTL23 selects its substrates and whether its transcriptional co-activator role and its histone methyltransferase role are mechanistically unified remains unresolved.
• No structural model of catalysis or substrate recognition
• Relationship between GABPA co-regulation and H3R17 methylation untested
• Full substrate repertoire undefined