PRMT5 - the type II arginine methyltransferase this graph has reached for sixteen times, whose mark on H3R2 RECRUITS WDR5 to chromatin

This is a prediction, not a measurement. No one has seen this protein in this shape. The colours say how much the software trusts itself, and that is worth reading before anything else — the orange stretches are places the model is effectively saying this part has no fixed shape.

• Essential-function toxicity: PRMT5 is required by 94.8% of 1,258 DepMap lines with a mean gene effect of -1.1947, and its obligate partner WDR77 is comparably essential. This is the regime in which the type I PRMT inhibitor GSK3368715 was terminated for lack of efficacy AND dose-limiting toxicity (gene-prmt1).
• The clinical experiment in myeloid disease has already been stopped once: NCT03614728, GSK3326595 in MDS and AML, was TERMINATED at 30 participants on sponsor review of clinical data in the indication.
• Age: every PRMT5-inhibitor trial that reached myeloid disease set a minimum age of 18 years, so the infant t(4;11) population is outside the eligibility of the entire clinical programme and nothing about tolerability in an infant is known.
• Direction risk on the central substrate: in cardiomyocytes PRMT5 REPRESSES HOXA9, so PRMT5 inhibition RAISES HoxA9. If any of that sign carries into a haematopoietic cell, a PRMT5 inhibitor would be raising the output of the transcription factor this disease runs on.
• Resistance and compensation: H3R2me2s is written by PRMT5 AND PRMT7, and H4R3 is methylated asymmetrically by PRMT1 and PRMT3 as well. A single-enzyme inhibitor can leave the residue modified by a paralogue - and because the asymmetric product has the OPPOSITE effect on WDR5, paralogue compensation here does not merely blunt the drug, it can invert the readout.
• Delivery and combination: the one positive fusion-relevant result is a PRMT5-plus-DOT1L-inhibitor synergy in an engineered cord-blood model. DOT1L inhibition alone already failed to deliver durable responses in the clinic (drug-pinometostat), so the combination inherits two agents with thin single-agent records rather than one strong one.
• Selectivity is the wrong way round: this project's own scan puts PRMT5 in the 95.9th percentile of the ANTI-selective tail for KMT2A-rearranged lines. Any therapeutic argument here has to rest on absolute dependency rather than fusion selectivity, and that argument applies equally to every other leukaemia.

1. Is H3R2me2s present at KMT2A::AFF1 target loci, and does it track WDR5 occupancy there? Nobody has measured either arginine mark at a fusion target in any lineage, and the two writers - PRMT5 and PRMT6 - push WDR5 in opposite directions.
2. Does PRMT5 inhibition displace WDR5 from chromatin in a t(4;11) line? If H3R2me2s recruits WDR5 to the H3 tail, a PRMT5 inhibitor is an indirect WRAD-recruitment inhibitor, which is a completely different rationale from the anti-proliferative one the trials were run on.
3. Is HOXA9 Arg-140 symmetrically dimethylated in a KMT2A-rearranged blast, and does it matter? The residue and the enzyme are both known; the experiment has only ever been done in endothelial cells, and in cardiomyocytes the sign is reversed.
4. Why is PRMT5 anti-selective in the KMT2A arm (rank 17,006 of 17,728) if the PAF complex - which KMT2A fusions bind directly - is its transcriptional activator? One possibility is that PRMT5 levels are already saturating for function in every leukaemia; another is that the PAFc route is a property of mouse MLL-AF9.
5. Does the 4.5-day survival extension scale with anything? Both the knockdown arm and the inhibitor arm gave +4.5 days in mice that all still died of leukaemia. Before any combination is proposed it is worth knowing whether that is a ceiling set by the biology or by the dosing.
6. Where is PRMT5 in a t(4;11) blast? Four coded compartments including Chromosome and Golgi, no subnuclear assignment, and a nucleolar pool implied only by its substrate. One fractionation would tell us whether the chromatin argument in this entry has a chromatin pool to run on.

1. E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

   PRMT5 (O14744, 637 aa) is a type II protein arginine methyltransferase forming monomethyl- and SYMMETRIC dimethyl-arginine, is a component of the methylosome with WDR77 and CLNS1A, methylates the Sm proteins SNRPD1 and SNRPD3 as a requirement for snRNP core assembly, and carries four experimentally coded subcellular locations - Cytoplasm, Nucleus, Chromosome and Golgi apparatus - with a SAM-dependent MTase PRMT-type domain at 308-615, a TIM barrel at 13-292 and a beta barrel at 465-637.

   UniProtKB O14744 (ANM5_HUMAN), Protein arginine N-methyltransferase 5 - FUNCTION, CATALYTIC ACTIVITY, SUBUNIT, SUBCELLULAR LOCATION and feature table, fetched 2026-09-22 · UniProt Consortium 2026
   ▸What this evidence cannot show

   A database record, not a measurement. The SUBUNIT block is a single 2,301-character paragraph carrying 27 evidence codes for dozens of sentences, so an individual interaction sentence inside it - for instance the bare sentence 'Interacts with HOXA9' - cannot be attributed to a specific paper from the record alone. Rule 91 therefore applies and the HOXA9 claim in this entry is cited to its own primary paper (E4), not to UniProt. The accession is asserted explicitly rather than confirmed by a length readback, because PRMT1 (371 aa) and PRMT6 (375 aa) sit four residues apart and this family defeats a length check.

   ▸Evidence that argues against this (1)

   • UniProt's own FUNCTION text says PRMT5 has 'a preference for the formation of MMA' - monomethyl-arginine - over symmetric dimethyl-arginine, and it weights the histone activities lower than the non-histone ones: methylation of histone H2A/H4 Arg-3 and of H3 Arg-8 are both annotated BY SIMILARITY, while the Sm D1/D3 symmetric dimethylation carries three experimental citations. The database's own evidence weighting therefore makes PRMT5 better established as a spliceosome enzyme than as a histone enzyme in human cells, which is the opposite of the emphasis a chromatin-focused entry naturally takes. UniProt Consortium 2026
2. E2moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper

   In murine MLL-AF9 AML the PAF complex is a direct transcriptional activator of the Prmt5 locus - CDC73 and LEO1 occupy the PRMT5 TSS with RNA Pol II in the human MLL-AF9 line THP-1, PRMT5-mediated H4R3me2s falls after conditional Cdc73 excision, and the activating unit named is PAFc plus MLL1 plus HOXA9 plus STAT5 - and Prmt5 knockdown or EPZ015666 caused a G1 arrest and extended median survival by 4.5 days.

   The PAF complex regulation of Prmt5 facilitates the progression and maintenance of MLL fusion leukemia. · Serio J, Ropa J, Chen W, Mysliwski M, Saha N, Chen L, Wang J, Miao H, Cierpicki T, Grembecka J, Muntean AG · Oncogene 2018
   PMID 28945229DOI
   ▸What this evidence cannot show

   The system is murine MLL-AF9 (MA9-Cdc73fl-CreER) plus a Hoxa9/Meis1 overexpression model. Full text read from Europe PMC (PMC5785415) on 2026-09-22: the string MLL-AF4 appears ZERO times. The human cells are THP-1 (a public ChIP-seq re-analysis, not a new experiment), U937, NB4 and MonoMac6 - none of them a t(4;11) line. The in vivo effect is small and non-curative: median survival +4.5 days by knockdown and +4.5 days by EPZ015666, with every moribund animal still dying of leukaemia. And the result is about the PRMT5 GENE being a PAFc target, not about PRMT5 protein being in a fusion complex - no PRMT5-KMT2A physical contact is reported anywhere.

   ▸Evidence that argues against this (1)

   • This project's own genome-wide DepMap scan places PRMT5 at rank 17,006 of 17,728 for KMT2A-rearranged selectivity - the 95.9th percentile of the anti-selective tail, with KMT2A-rearranged lines at -1.2344 against -1.3403 in other leukaemia lines. If PRMT5 sat downstream of an MLL-fusion-specific transcriptional unit, the KMT2A-rearranged arm should need it MORE, not marginally less. WDR77/MEP50, PRMT5's obligate methylosome partner, shows the same direction (rank 15,455, -1.5903 against -1.6503), so the signal is complex-level and consistent. The compatible reading is that PRMT5 is a general leukaemia dependency the PAFc happens to supply, not a fusion-created one. Broad Institute DepMap via Open Targets Platform 2026
3. E3strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

   Histone H3 Arg-2 is symmetrically dimethylated by PRMT5 and PRMT7 to give H3R2me2s, a euchromatic mark that ENHANCES binding of WDR5 - a shared component of the MLL, SET1A, SET1B and ATAC coactivator complexes - and EXCLUDES binding of RBBP7, a central subunit of the Sin3a, NuRD and PRC2 corepressor complexes; this is the opposite of PRMT6's asymmetric H3R2me2a, which impedes WDR5 recruitment to chromatin and antagonises H3K4 trimethylation.

   Symmetric dimethylation of H3R2 is a newly identified histone mark that supports euchromatin maintenance. · Migliori V, Muller J, Phalke S, Low D, Bezzi M, Mok WC, Sahu SK, Gunaratne J, Capasso P, Bassi C, Cecatiello V, De Marco A, Blackstock W, Kuznetsov V, Amati B, Mapelli M, Guccione E · Nature Structural and Molecular Biology 2012
   PMID 22231400DOI
   ▸What this evidence cannot show

   Human cells, but the systems are HeLa and NT2 differentiation - not haematopoietic, and not any fusion. The WDR5 affinity result is an H3-tail peptide and SILAC-MS interactor result plus a peptide co-crystal; it is not a demonstration that H3R2me2s recruits an intact MLL/COMPASS complex to a gene, and certainly not in a KMT2A-fusion cell. PRMT7 is a second writer of the same mark and has no entry in this graph, so the mark must not be attributed to PRMT5 alone.

   ▸Evidence that argues against this (2)

   • The whole idea that H3R2 arginine marks matter by gating WDR5 depends on WDR5's H3-tail binding being functionally load-bearing for KMT2A, and the structurally defined KMT2A-WDR5 contact is not a histone-tail contact at all: it is the WIN motif, a short arginine-containing peptide from the SET-domain region of the KMT2 protein inserting into WDR5's central channel. If WDR5 recruitment to a KMT2A fusion runs through a WIN motif that most fusions have LOST along with the SET domain, then an H3R2 mark modulating WDR5's histone-tail affinity may be irrelevant to the chimera even where it matters for wild-type COMPASS. This graph's own `concept-wdr5-what-is-established-for-wild-type-kmt2a-and-what-for-the-fusion` exists precisely to keep those two cases apart. Dharmarajan V et al. 2012
   • SUPERSEDED IN DIRECTION, and the superseding paper names this one. PMID 32207970 (Lorton BM, et al., 'A Binary Arginine Methylation Switch on Histone H3 Arginine 2 Regulates Its Interaction with WDR5', Biochemistry, doi 10.1021/acs.biochem.0c00035) states in its own abstract that previous studies suggested H3R2me2s specified a high-affinity interaction with WDR5, and then, using quantitative binding analysis with high-resolution crystal structures of WDR5 bound to unmodified, me1 and me2s arginine, reports a BINARY switch: H3R2me2a PREVENTS the WDR5 interaction while H3R2me0, me1 and me2s are EQUALLY PERMISSIVE. So H3R2me2s does not enhance WDR5 binding over unmodified chromatin; it relieves a block that me2a imposes. The claim above is an accurate report of PMID 22231400 and should be read as the superseded model. Verified by efetch 2026-09-22. THE CONSEQUENCE IS THERAPEUTIC AND OPPOSITE: a graded switch says ACTIVATE PRMT5 to gain WDR5 recruitment, while a binary switch says the only available move is to INHIBIT PRMT6 and relieve the block, because no intervention can push binding above the unmodified baseline. The RBBP7 exclusion in this evidence item is NOT affected by that paper and stands as written.
4. E4moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper

   PRMT5 symmetrically dimethylates the homeobox transcription factor HOXA9 at Arg-140: PRMT5 was identified as a TNF-alpha-dependent HOXA9 binding partner by mass spectrometry in endothelial cells, is recruited to the E-selectin promoter following transient HOXA9 binding, and that methylation event is essential for E-selectin and VCAM-1 induction.

   HOXA9 methylation by PRMT5 is essential for endothelial cell expression of leukocyte adhesion molecules. · Bandyopadhyay S, Harris DP, Adams GN, Lause GE, McHugh A, Tillmaand EG, Money A, Willard B, Fox PL, DiCorleto PE · Molecular and Cellular Biology 2012
   PMID 22269951DOI
   ▸What this evidence cannot show

   Human endothelial cells under TNF-alpha: an inflammation system with no haematopoietic or leukaemic arm at all, and readouts (E-selectin, VCAM-1) that are not a HOX program. Transfer to KMT2A-fusion leukaemia is an inference from shared substrate identity and nothing more - HOXA9 R140 methylation has never been measured in any leukaemia cell, and `PRMT5[tiab] AND HOXA9[tiab]` returns only 3 records in total.

   ▸Evidence that argues against this (1)

   • The direction of the PRMT5-HOXA9 relationship reverses in another tissue. In cardiomyocytes PRMT5 symmetrically dimethylates HoxA9 AND REPRESSES HoxA9 expression, so that silencing or inhibiting PRMT5 RAISES HoxA9 and worsens hypertrophy, while PRMT5 overexpression suppresses it. Read that way PRMT5 is a restraint on HOXA9 rather than a co-activator of it, which predicts that PRMT5 inhibition would INCREASE HOXA9 output - the opposite of what a PRMT5-inhibitor strategy in a HOXA9-driven leukaemia assumes. Cai S et al. 2020
5. E5moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper

   In a CRISPR/Cas9 umbilical-cord-blood model of 100% pure MLL-AF4- or MLL-AF9-rearranged human cells, PRMT5 and DOT1L inhibitors each reduced proliferation dose-dependently, impaired the cell cycle, increased differentiation and apoptosis, downregulated target genes and sensitised to chemotherapy - and the combination of the two was SYNERGISTIC.

   Inhibition of DOT1L and PRMT5 promote synergistic anti-tumor activity in a human MLL leukemia model induced by CRISPR/Cas9. · Secker KA, Keppeler H, Duerr-Stoerzer S, Schmid H, Schneidawind D, Hentrich T, Schulze-Hentrich JM, Mankel B, Fend F, Schneidawind C · Oncogene 2019
   PMID 31417187DOI
   ▸What this evidence cannot show

   This is the ONLY record returned by `PRMT5[tiab] AND MLL-AF4[tiab]` (= 1, 2026-09-22), and the abstract does not separate the MLL-AF4 arm from the MLL-AF9 arm for the PRMT5 result, so 'shown in MLL-AF4' cannot be asserted at arm level from the abstract; the full text was not read for this entry, so this evidence item is abstract-level only. The model is engineered cord-blood CD34+ material, not infant patient cells, and the synergy is a culture proliferation readout with no in vivo or patient arm.

   ▸Evidence that argues against this (1)

   • A synergy result between two epigenetic inhibitors in an engineered line is the weakest form of evidence for a combination, because both single agents are anti-proliferative in almost any dividing cell and PRMT5 is required by 94.8% of DepMap lines. The clinical experiment closest to this has been run and stopped: NCT03614728, a phase I/II of the PRMT5 inhibitor GSK3326595 in myelodysplastic syndrome and acute myeloid leukaemia, was TERMINATED after 30 actual participants, the sponsor's stated reason being an internal review of clinical data in the context of the indication under investigation. Synergy in a cord-blood model did not survive contact with myeloid patients. ClinicalTrials.gov 2022
6. E6strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.database

   PRMT5 is flagged essential in DepMap CRISPR (Chronos) with a mean gene effect of -1.1947 across 1,258 screened cell lines and 94.8% of lines depleted below -0.5; in lymphoid tissue specifically the mean is -1.2246 over 97 lines, of which 13 are B-cell acute lymphoblastic leukaemia lines.

   DepMap CRISPR (Chronos) gene effect served through the Open Targets Platform GraphQL API, field depMapEssentiality, fetched 2026-09-22 with approvedSymbol read back as PRMT5 · Broad Institute DepMap via Open Targets Platform 2026
   ▸What this evidence cannot show

   Rule 83: the Open Targets GraphQL response does NOT state the DepMap release, so the release is unverified and only the fetch date is on record; the screen count of 1,258 is PRMT5's own and must not be read as a corpus-wide denominator. The approvedSymbol was read back to confirm the Ensembl id resolved correctly - a sibling lookup in the same call resolved ENSG00000116157 to GPX7 rather than the intended WDR77, which is exactly what the readback is for, and no WDR77 figure is quoted from that call. The lymphoid-tissue bucket is a tissue label, not a KMT2A-status label; no line in it is identified as t(4;11) by this query.

   ▸Evidence that argues against this (1)

   • A near-pan-essential gene is a poor oncology target on its own terms, and this graph has already made that argument once for a PRMT: PRMT1 is depleted in 98.7% of lines and the first-in-human type I PRMT inhibitor was terminated for lack of efficacy AND dose-limiting toxicity. PRMT5 at 94.8% is in the same regime and its methylosome partner WDR77 is comparably essential, so a therapeutic window has to come from something other than differential expression - in practice from MTAP deletion, and this project's own analysis found the KMT2A-rearranged arm is NOT MTAP-deleted. Zhu Y et al. 2019
7. E7established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.trial_registry

   Two PRMT5-inhibitor trials reached myeloid patients: NCT03614728 (GSK3326595 with and without 5-azacitidine, phase I/II, myelodysplastic syndrome and AML) was TERMINATED with 30 actual participants for an internal review of clinical data in the context of the indication; NCT03886831 (PRT543, phase I) COMPLETED with 232 actual participants across cohorts that included relapsed/refractory AML and refractory chronic myelomonocytic leukaemia. Both set a minimum age of 18 years.

   ClinicalTrials.gov API v2 records for NCT03614728 and NCT03886831 - overallStatus, whyStopped, phases, enrollmentInfo, conditions and minimumAge, fetched 2026-09-22 · ClinicalTrials.gov 2026
   NCT03614728
   ▸What this evidence cannot show

   A registry record states status and the sponsor's stated reason for stopping; it does not report efficacy, and 'terminated due to internal review of clinical data in context of indication under investigation' is not a statement that the drug failed. Neither trial enrolled a KMT2A-rearranged cohort as such, and neither could enrol an infant - the minimum age is 18 years in both - so the population this project exists for is outside the eligibility of every PRMT5 inhibitor that has reached myeloid disease. Registry-only: no publication was read for either trial.

   ▸Evidence that argues against this (1)

   • Reading the whole PRMT5 clinical picture off two myeloid trials understates the class, and the understatement runs in an unusual direction: the MTA-cooperative second generation (MRTX1719, AMG 193) is built for MTAP-deleted tumours and is where the class's activity now sits, which makes the myeloid programme's fate weak evidence about PRMT5 inhibition in general and strong evidence that undifferentiated PRMT5 inhibition in myeloid disease is hard. Measured 2026-09-22 with translations read back: MRTX1719[tiab] = 15, AMG 193[tiab] = 5, GSK3326595[tiab] = 38, JNJ-64619178[tiab] = 15, onametostat[tiab] = 3; none of these is in a KMT2A-rearranged indication. NCBI PubMed 2026
8. E8strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.database

   PRMT5's KMT2A-fusion literature is reachable only through three different names for the same disease - PRMT5[tiab] AND MLL[tiab] = 18, AND KMT2A[tiab] = 2, AND MLL-AF9[tiab] = 2, AND MLL-AF4[tiab] = 1 - while AND MEIS1[tiab] = 0, AND infant[tiab] = 0 and AND B-ALL[tiab] = 0.

   NCBI E-utilities esearch, db=pubmed, counts with querytranslation and warninglist read back, run 2026-09-22; every load-bearing zero run twice · NCBI PubMed 2026
   ▸What this evidence cannot show

   A PubMed count bounds titles and abstracts only; rule 80 applies and these zeros say nothing about supporting figures. Three of these zeros were first returned with an EMPTY querytranslation - the transient instrument failure of registry row 123 - and were confirmed as genuine only on re-run; the values recorded here are the re-run values, each of which returned a fully parsed translation together with warninglist.outputmessages = ['No items found.']. Every count uses one tag per term (rule 94), never the grouped form.

   ▸Evidence that argues against this (1)

   • These counts understate PRMT5's reach into this disease in a way no name list fixes, because the relevant datum can be full-text only. The same PAFc paper that is this entry's anchor also reports that PRMT5, PRMT1 AND PRMT3 are all significantly downregulated after loss of either CDC73 or PAF1 - and that PRMT3 result is invisible to every PRMT3 query, since PRMT3[tiab] AND MLL[tiab] returns 1 record and it is a fluorescence assay-development paper, while PRMT3[tiab] AND CDC73[tiab] and PRMT3[tiab] AND PAFc[tiab] both return 0 with fully parsed translations. A counted zero over abstracts can sit directly on top of a positive result in the body of a paper the same beat has already read. Serio J et al. 2018

• regulates →WDR5 — the partner that is not a partner: it binds the half of KMT2A the fusion throws away

  H3R2me2s ENHANCES WDR5 binding to the H3 tail; H3R2me2a impedes it

• regulates →RBBP7 - the silent paralogue that is not silent, and the reason this project's paralogue rule finally produced a positive answer

  H3R2me2s EXCLUDES RBBP7 from the H3 tail (Sin3a/NuRD/PRC2 subunit)

• depends on →CDC73 / parafibromin — the PAF1C subunit that was genetically tested, and a second tumour suppressor required by the fusion

  PRMT5 transcription is directly activated by the PAF complex in MLL-AF9 AML

• depends on →PAF1 — pan-essential subunit of a complex the fusion needs, where the window is in the interface and not in the protein

  PAF1 knockdown in THP-1 downregulates PRMT5

• related to →LEO1 — the weakest-evidenced entry in the PAF1 complex, and the gene whose Ensembl id this project already got wrong once

  LEO1 and CDC73 peaks over the PRMT5 TSS in THP-1

• binds →HOXA9 — required for survival of established MLL-rearranged leukemia, and dispensable for starting it

  TNF-dependent HOXA9 partner; symmetrically dimethylates HOXA9 Arg-140

• related to →KMT2A / MLL1 — the gene that breaks

  MLL1 is named in the PAFc/HOXA9/STAT5 unit activating PRMT5; no physical contact reported

• related to →KMT2A::AFF1 (MLL-AF4), t(4;11)(q21;q23)

  PRMT5 + DOT1L inhibitor synergy in a CRISPR MLL-AF4 cord-blood model; the only MLL-AF4 record

• related to →DOT1L — the target where excellent chemistry met an indirect interaction

  PRMT5 and DOT1L inhibitors are synergistic in MLL-AF4/AF9 cord-blood cells

• related to →Pinometostat (EPZ-5676) — the DOT1L inhibitor, and the most instructive failure in this field

  the DOT1L arm of the only fusion-relevant PRMT5 combination

• related to →The MTAP-deleted, MTA-high state - a genotype-imposed metabolic state that this project's KMT2A-rearranged arm turns out NOT to have, and that its own screen could never have detected directly

  the MTA/PRMT5 synthetic-lethal state; NB4 (low MTAP) was the most inhibitor-sensitive line

• depends on →SAM / methionine dependence - the one metabolic state in this graph demonstrated in KMT2A-rearranged lymphoblastic leukaemia itself, with a drug and a PDX behind it

  PRMT5 is a SAM-consuming methyltransferase

• related to →MAT2A - the enzyme that makes the methyl donor, and the one metabolic dependency in this disease with two independent papers and a lymphoid PDX result

  MAT2A supplies the SAM PRMT5 consumes; the MTAP/MAT2A/PRMT5 axis

• ← regulatesEPB41L3 / DAL-1 - a membrane-skeleton tumour suppressor that binds and modulates two arginine methyltransferases, and whose own promoter methylation is a clinical test

  DAL-1/4.1B modulates PRMT5 substrate-specifically (inhibits Sm, enhances MBP)

• part of →Menin represses GLP1R - the receptor a whole class of diabetes drugs exists to switch on

  the menin-PRMT5 complex this graph already holds

• related to →PRMT1 — an MLL-fusion cofactor whose first-in-human inhibitor was terminated for lack of efficacy and toxicity

  paralogue and a documented conflation hazard in the MLL literature

• related to →WDR5: an established wild-type KMT2A contact, and no fusion contact ever measured

  an arginine mark that gates WDR5 is a WRAD-recruitment lever that adjudication does not consider

• related to →WDR5 WIN site and KMT2A Arg3765: measured at 1.7 uM, three co-crystals, and absent from every leukaemic fusion - plus the MLL3 peptide that binds it 51-fold tighter

  the competing WDR5 route: a WIN-motif protein interface rather than a histone-tail interface

• related to →TP53 - named in 84 entries of this graph, absent from the index genome study of the disease, and four different things depending on when you look

  both PRMT5 and EHMT2 methylate non-histone substrates including p53

• related to →Plain-English: chromatin and epigenetics — the sticky notes on the DNA, and which ones matter here

  arginine methylation as a chromatin mark class

• ← related toPRMT6 - the enzyme whose mark is MUTUALLY EXCLUSIVE with the MLL complex on the H3 tail, and which shuts HOX genes down by evicting WDR5

  opposite dimethyl states of the SAME residue H3R2, with opposite effects on WDR5

• related to →ING2 - the PHD finger that reads H3K4me3 and turns it into REPRESSION, and whose founding co-crystal is filed under the MOUSE accession

  H3R2me2s excludes RBBP7, a subunit of the corepressor ING2 carries

• ← related toPRMT3 - the mostly-cytoplasmic ribosome methyltransferase that also writes the ACTIVATING mark on the residue PRMT5 represses, has an acute-leukaemia degrader, and is invisible to this project's own mark-query rule

  opposite dimethyl states of the SAME residue H4R3 - me2a activating against me2s repressive

• causes →H3R2me2s - the symmetric mark on the SAME residue as H3R2me2a, which permits rather than enhances WRAD access, and whose 'enhancing' half this graph inherited from the paper that was later revised

  type II writer of the symmetric state on H3 Arg-2; established

• causes →H4R3me2s - the repressive symmetric arginine mark that recruits DNMT3A, blocks a KMT2 enzyme's own PHD module, and is the ONLY arginine mark ever measured in a KMT2A-fusion system

  writer at the beta-globin locus in primary human erythroid progenitors, and the writer whose abundance sets the mark in murine MLL-AF9

• ← related toPRMT7 - the enzyme whose class is still disputed, which represses a KMT2 enzyme by writing H4R3me2s, which is required for leukaemia stem cells in CML, and whose only H3R2 claim is the one this beat was dispatched to check

  the two symmetric-dimethyl candidates, experimentally SEPARATED: PRMT7 and not PRMT5 raises H4R3me2s at KMT2D targets, while PRMT5 is the writer at globin and in MLL-AF9