m6A-centered Crosstalk Information

Mechanism of Crosstalk between m6A Modification and Epigenetic Regulation
Crosstalk ID
M6ACROT05971
 [1]
m6A modification LncRNA NORAD LncRNA NORAD WTAP Methylation : m6A sites Direct Inhibition Non-coding RNA lncRNA NORAD PUM2  lncRNA       miRNA   circRNA
m6A Modification:
m6A Regulator Wilms tumor 1-associating protein (WTAP) WRITER
 Regulator Info 
m6A Target Long intergenic non-protein coding RNA 657 (NORAD)
 Targert Gene 
Epigenetic Regulation that have Cross-talk with This m6A Modification:
Epigenetic Regulation Type Non-coding RNA (ncRNA)
Epigenetic Regulator Long intergenic non-protein coding RNA 657 (NORAD) LncRNA View Details
Regulated Target Pumilio homolog 2 (PUM2) View Details
Crosstalk Relationship m6A  →  ncRNA Inhibition
Crosstalk Mechanism m6A regulators directly modulate the functionality of ncRNAs through specific targeting ncRNA
Crosstalk Summary Subsequent loss- and gain-of-function experiments reveal WTAP is increased in senescent nucleus pulposus cells, and significantly promotes Long intergenic non-protein coding RNA 657 (NORAD) m6A modification. YTHDF2-mediated decay of NORAD is enhanced in senescent NPCs, and then deficiency of NORAD results in less sequestraion of PUMILIO proteins, contributing to the augmented activity of PUM1 and Pumilio homolog 2 (PUM2), thus repressing the expression of target E2F3 mRNAs and promoting the cellular senescence. This study shows interruption of NORAD m6A modification or the NORAD/PUMILIO/E2F3 axis could serve as a potential therapeutic target to inhibit the senescence of NPCs and development of intervertebral disc degeneration(IVDD).
Responsed Disease Intervertebral disc degeneration ICD-11: FA80
 Disease Info 
In-vitro Model
 Nucleus pulposus cells (NPCs) (Nucleus pulposus cells)
In-vivo Model After 50g male NORAD-KO or C57 mice at age of 8 weeks were anesthetized with 3% (w/v) pentobarbital (2 ml/kg) and grouped randomly, investigators blinded to the group allocation performed the experiment. The disc levels in rat tail (Co6/7, 7/8, and 8/9) were located by palpation on the coccygeal vertebrae and confirmed by trial radiography. Needles (33-G) were used to puncture the annulus fibrosus layer though the tail skin, in parallel to the end plates. To ensure that the needle did not penetrate too deeply , the length of the needle was pre-determined according to the dimensions of annulus fibrosus and the NP , which were measured in a preliminary experiment and found to be approximately 4 mm. Five kinds of solution were prepared for intradisc injection, including AA V vector, AAV containing shPUM1, AAV containing shPUM2 for Norad KO mice, AAV vector, AAV containing shE2F3, AAVcontaining OE-E2F3 for WT mice.
Full List of Potential Compound(s) Related to This m6A-centered Crosstalk
FA80: Intervertebral disc degeneration 3 Compound(s) Regulating the Disease Click to Show/Hide the Full List
 Compound Name Rexlemestrocel-L Phase 3 [2]
Synonyms
MPC-150-M
    Click to Show/Hide
External Link
TTD: DHV2L8
 Compound Name CybroCell Phase 1/2 [3]
External Link
TTD: DS6C1Y
 Compound Name IDCT Phase 1/2 [4]
Synonyms
rebonuputemcel
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External Link
TTD: DK65RJ
References
Ref 1 WTAP-mediated m(6)A modification of lncRNA NORAD promotes intervertebral disc degeneration. Nat Commun. 2022 Mar 18;13(1):1469. doi: 10.1038/s41467-022-28990-6.
Ref 2 ClinicalTrials.gov (NCT02412735) Placebo-controlled Study to Evaluate Rexlemestrocel-L Alone or Combined With Hyaluronic Acid in Subjects With Chronic Low Back Pain (MSB-DR003). U.S. National Institutes of Health.
Ref 3 Clinical pipeline report, company report or official report of FibroGenesis.
Ref 4 ClinicalTrials.gov (NCT03955315) Study to Evaluate the Safety and Preliminary Efficacy of IDCT, a Treatment for Symptomatic Lumbar Disc Degeneration. U.S. National Institutes of Health.