m6A-centered Crosstalk Information

Mechanism of Crosstalk between m6A Modification and Epigenetic Regulation
Crosstalk ID
M6ACROT03088
 [1]
m6A modification Kat2a Kat2a ALKBH5 Demethylation : m6A sites Direct Inhibition Histone modification H3K27ac Kat2a TFRC
m6A Modification:
m6A Regulator RNA demethylase ALKBH5 (ALKBH5) ERASER
 Regulator Info 
m6A Target Histone acetyltransferase KAT2A (KAT2A)
 Targert Gene 
Epigenetic Regulation that have Cross-talk with This m6A Modification:
Epigenetic Regulation Type Histone modification (HistMod)
Epigenetic Regulator Histone acetyltransferase KAT2A (KAT2A) WRITER View Details
Regulated Target Histone H3 lysine 27 acetylation (H3K27ac) View Details
Downstream Gene TFRC 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 ALKBH5 was found to reduce m6A methylation levels on Histone acetyltransferase KAT2A (KAT2A) mRNA, leading to its upregulation. YTHDF2 played a crucial role as an m6A reader protein mediating the degradation of Kat2a mRNA. Furthermore, Kat2a promoted ferroptosis by increasing TFRC and Hmox1 expression via enhancing the enrichment of Histone H3 lysine 27 acetylation (H3K27ac) and H3K9ac on their promoter regions. In conclusion, our findings unveil a novel role for the Kat2a-ferroptosis axis in DCM pathogenesis, providing valuable insights for potential clinical interventions.
Responsed Disease Diabetic cardiomyopathy ICD-11: BC43.7
 Disease Info 
In-vitro Model
 NMVMs (Primary neonatal mouse ventricular myocytes)
In-vivo Model For cardiomyocyte-specific Kat2a knockdown in vivo, a total of 100 μl (5.0 × 1013 VG/ml) adeno-associated virus 9 (AAV9) carrying shRNA against Kat2a (AAV-shKat2a) was randomly applied per mouse via tail vein injection. AAV9 carrying scramble shRNA (AAV-shNC) was used as control. Cardiac function was assessed four weeks following the AAV injection, and the heart tissues were then isolated.
Full List of Potential Compound(s) Related to This m6A-centered Crosstalk
Transferrin receptor protein 1 (TFRC) 2 Compound(s) Regulating the Target Click to Show/Hide the Full List
 Compound Name CX2029 Phase 1/2 [2]
External Link
TTD: DZ1F3N
 Compound Name ABBV-CX-2029 Phase 1 [3]
External Link
TTD: D58AMF
BC43: Cardiomyopathy 3 Compound(s) Regulating the Disease Click to Show/Hide the Full List
 Compound Name Levosimendan Approved [4]
Synonyms
Levosimedan; Levosimendanum; Simdax; Levosimendan [INN]; Simdax (TN); Levosimendan (USAN/INN); Mesoxalonitrile(p-((R)-1,4,5,6-tetrahydro-4-methyl-6-oxo-pyridazinyl)phenyl)hydrazone; Mesoxalonitrile (-)-(p((R)-1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl)hydrazone; ((4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl)hydrazono)propanedinitrile; (-)-OR-1259; (R)-((4-(1,4,5,6-Tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl)hydrazono) propanedintrile; (R)-((4-(1,4,5,6-Tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl)hydrazono)propanedinitrile; ({4-[(4R)-4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl]phenyl}hydrazono)propanedintrile; 2-[[4-[(4R)-4-methyl-6-oxo-4,5-dihydro-1H-pyridazin-3-yl]phenyl]hydrazinylidene]propanedinitrile
    Click to Show/Hide
External Link
CID: 3033825
TTD: D0C4HG
DrugBank: DB00922
 Compound Name ALN-TTRsc Phase 3 [5]
Synonyms
SAR438714
    Click to Show/Hide
External Link
TTD: D0E9AF
 Compound Name PB1046 Phase 1 [6]
Synonyms
Pemziviptadil; PB1046 Vasomera; PB-1120 Vasomera
    Click to Show/Hide
External Link
TTD: D0G9JQ
References
Ref 1 Histone acetyltransferase Kat2a regulates ferroptosis via enhancing Tfrc and Hmox1 expression in diabetic cardiomyopathy. Cell Death Dis. 2024 Jun 10;15(6):406. doi: 10.1038/s41419-024-06771-x.
Ref 2 Nonclinical Efficacy and Safety of CX-2029, an Anti-CD71 Probody-Drug Conjugate. Mol Cancer Ther. 2022 Aug 2;21(8):1326-1336.
Ref 3 Clinical pipeline report, company report or official report of AbbVie.
Ref 4 Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
Ref 5 ClinicalTrials.gov (NCT02319005) ENDEAVOUR: Phase 3 Multicenter Study of Revusiran (ALN-TTRSC) in Patients With Transthyretin (TTR) Mediated Familial Amyloidotic Cardiomyopathy (FAC). U.S. National Institutes of Health.
Ref 6 Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)