m6A-centered Crosstalk Information

Mechanism of Crosstalk between m6A Modification and Epigenetic Regulation
Crosstalk ID
M6ACROT03015
 [1]
m6A modification KDM6B KDM6B METTL3 Methylation : m6A sites Direct Inhibition Histone modification H3K27me3 KDM6B IL6
m6A Modification:
m6A Regulator Methyltransferase-like 3 (METTL3) WRITER
 Regulator Info 
m6A Target Lysine-specific demethylase 6B (KDM6B)
 Targert Gene 
Epigenetic Regulation that have Cross-talk with This m6A Modification:
Epigenetic Regulation Type Histone modification (HistMod)
Epigenetic Regulator Lysine-specific demethylase 6B (KDM6B) ERASER View Details
Regulated Target Histone H3 lysine 27 trimethylation (H3K27me3) View Details
Downstream Gene IL6 View Details
Crosstalk Relationship m6A  →  Histone modification Inhibition
Crosstalk Mechanism m6A modification impacts directly histone modification through modulating the expression level of histone-associated enzymes
Crosstalk Summary The mRNA of Lysine-specific demethylase 6B (KDM6B) was m6A-modified by METTL3/METTL14 and its decay mediated by YTHDF2. YTHDF2 deficiency stabilized KDM6B to promote Histone H3 lysine 27 trimethylation (H3K27me3) demethylation of multiple proinflammatory cytokines and subsequently enhanced their transcription. Knockout (KO) of YTHDF2, an m6A reader, markedly enhanced demethylation of H3K27me3 on the promoters of proinflammatory cytokines (e.g., IL6 and IL-12B). Furthermore, we identified H3K27me3 as a barrier for m6A modification during transcription. KDM6B recruits the m6A methyltransferase complex to facilitate the methylation of m6A in transcribing mRNA by removing adjacent H3K27me3 barriers. These results revealed cross-talk between m6A and H3K27me3 during bacterial infection, which has broader implications for deciphering epitranscriptomics in immune homeostasis.
Responsed Disease Inflammatory response ICD-11: MG46
 Disease Info 
Cell Process RNA decay
In-vitro Model
 THP-1 Childhood acute monocytic leukemia Homo sapiens CVCL_0006
HEK293T Normal Homo sapiens CVCL_0063
Full List of Potential Compound(s) Related to This m6A-centered Crosstalk
Interleukin 6 (IL6) 15 Compound(s) Regulating the Target Click to Show/Hide the Full List
 Compound Name Siltuximab Approved [2]
External Link
TTD: D07NJN
 Compound Name Olokizumab Phase 3 [3]
MOA Modulator
External Link
TTD: D00NUG
 Compound Name Ziltivekimab Phase 3 [4]
MOA Inhibitor
External Link
TTD: DF86OC
 Compound Name RG6179 Phase 3 [5]
External Link
TTD: DWJM12
 Compound Name Sirukumab Phase 3 [6]
MOA Inhibitor
External Link
TTD: D01XVF
 Compound Name Clazakizumab Phase 2 [6]
MOA Inhibitor
External Link
TTD: D04RMM
 Compound Name CDP-6038 Phase 2 [7]
MOA Modulator
External Link
TTD: D07TCS
 Compound Name ALD-518 Phase 2 [7]
MOA Modulator
External Link
TTD: D0N0BW
 Compound Name YSIL6 Phase 2 [8]
MOA Inhibitor
External Link
TTD: D0VS2W
 Compound Name PF-04236921 Phase 2 [6]
MOA Inhibitor
External Link
TTD: D06NXG
 Compound Name Gerilimzumab Phase 1 [6]
External Link
TTD: D07IVS
 Compound Name MEDI5117 Phase 1 [9]
MOA Modulator
External Link
TTD: D0DT8Y
 Compound Name C326 Phase 1 [10]
MOA Inhibitor
External Link
TTD: D0GJ1U
 Compound Name OP-R003 Phase 1 [11]
Synonyms
VX-30; OP-R003-1; Elsilimomab derivative (hematological disease), OPi/Vaccinex; IL-6 antibodies (hematological disease), EUSA; IL6 antibodies (hematological disease), OPi/Vaccinex; OP-R003 (hematological cancer), GSK; OP-R003 (inflammation), GSK; Anti-IL-6 human MAb (hematological cancer), GSK; Anti-IL-6 human MAb(inflammation), GSK
    Click to Show/Hide
MOA Modulator
External Link
TTD: D0OK5R
 Compound Name SAR444419 Phase 1 [12]
External Link
TTD: DKX8W5
Lysine-specific demethylase 6B (KDM6B) 2 Compound(s) Regulating the Target Click to Show/Hide the Full List
 Compound Name GSK-J1 Investigative [13]
Synonyms
GSK J1; 1373422-53-7; 3-{[2-(pyridin-2-yl)-6-(2,3,4,5-tetrahydro-1H-3-benzazepin-3-yl)pyrimidin-4-yl]amino}propanoic acid; 3-((6-(4,5-Dihydro-1H-benzo[d]azepin-3(2H)-yl)-2-(pyridin-2-yl)pyrimidin-4-yl)amino)propanoic acid; 3-[[2-Pyridin-2-Yl-6-(1,2,4,5-Tetrahydro-3-Benzazepin-3-Yl)pyrimidin-4-Yl]amino]propanoic Acid; GSKJ1; MLS006010249; GTPL7027; SCHEMBL10157115; CHEMBL3188597; BDBM60875; EX-A571; AOB3940; CHEBI:131152; MolPort-023-278-906; EX-A1744; BCP08262; ZINC95616592; s7581; 2442AH; AKOS024458240
    Click to Show/Hide
MOA Inhibitor
Activity IC50 = 16 nM
External Link
CID: 56963315
TTD: D0S3DD
 Compound Name IOX1 Investigative [14]
Synonyms
5852-78-8; 8-Hydroxyquinoline-5-Carboxylic Acid; 8-Hydroxy-5-quinolinecarboxylic acid; 5-Carboxy-8-hydroxyquinoline; IOX 1; UNII-JM015YQC1C; IOX-1; 5-carboxy-8HQ; 5-Quinolinecarboxylic acid, 8-hydroxy-; JM015YQC1C; CHEMBL1230640; 4bio; 4jht; 8XQ; 4ie4; AC1LA0UV; MLS002729056; GTPL8230; SCHEMBL6068195; KS-00000PPH; CHEBI:93239; CTK1E0142; DTXSID20207236; AOB6499; JGRPKOGHYBAVMW-UHFFFAOYSA-N; MolPort-006-673-354; HMS3653E21; ZINC5933707; BCP16996; s7234; BDBM50396018; 2184AH; IOX1, > AKOS016371793
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MOA Inhibitor
Activity IC50 = 100 nM
External Link
CID: 459617
TTD: D0X5US
References
Ref 1 Interplay of m(6)A and H3K27 trimethylation restrains inflammation during bacterial infection. Sci Adv. 2020 Aug 19;6(34):eaba0647. doi: 10.1126/sciadv.aba0647. eCollection 2020 Aug.
Ref 2 2014 FDA drug approvals. Nat Rev Drug Discov. 2015 Feb;14(2):77-81. doi: 10.1038/nrd4545.
Ref 3 Efficacy and safety of olokizumab in patients with rheumatoid arthritis with an inadequate response to TNF inhibitor therapy: outcomes of a randomised Phase IIb study. Ann Rheum Dis. 2014 September; 73(9): 1607-1615.
Ref 4 IL-6 inhibition with ziltivekimab in patients at high atherosclerotic risk (RESCUE): a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet. 2021 May 29;397(10289):2060-2069.
Ref 5 Clinical pipeline report, company report or official report of Roche
Ref 6 Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
Ref 7 Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics. 2005 Aug;86(2):127-41. doi: 10.1016/j.ygeno.2005.04.008.
Ref 8 Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800020380)
Ref 9 Whole-molecule antibody engineering: generation of a high-affinity anti-IL-6 antibody with extended pharmacokinetics. J Mol Biol. 2011 Aug 26;411(4):791-807. doi: 10.1016/j.jmb.2011.06.031. Epub 2011 Jun 23.
Ref 10 The molecular basis of hepcidin-resistant hereditary hemochromatosis. Blood. 2009 Jul 9;114(2):437-43.
Ref 11 A high-affinity fully human anti-IL-6 mAb (OP-R003-1, 1339) for the treatment of Multiple Myeloma
Ref 12 Clinical pipeline report, company report or official report of Sanofi
Ref 13 A selective jumonji H3K27 demethylase inhibitor modulates the proinflammatory macrophage response. Nature. 2012 Aug 16;488(7411):404-8.
Ref 14 A cell-permeable ester derivative of the JmjC histone demethylase inhibitor IOX1. ChemMedChem. 2014 Mar;9(3):566-71. doi: 10.1002/cmdc.201300428. Epub 2014 Feb 6.