m6A-centered Crosstalk Information

Mechanism of Crosstalk between m6A Modification and Epigenetic Regulation
Crosstalk ID
M6ACROT05970
 [1]
m6A modification LncRNA NORAD LncRNA NORAD YTHDF2 : m6A sites Direct Inhibition Non-coding RNA lncRNA NORAD PUM1  lncRNA       miRNA   circRNA
m6A Modification:
m6A Regulator YTH domain-containing family protein 2 (YTHDF2) READER
 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 1 (PUM1) 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 Pumilio homolog 1 (PUM1) and 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
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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.