The Diminution of R-Loops Generated by LncRNA DSP-AS1 Inhibits DSP Gene Transcription to Impede the Re-Epithelialization During Diabetic Wound Healing.

Summary

The study identifies an epigenetic mechanism in diabetic wounds: reduced lncRNA DSP-AS1–mediated R-loop formation at the DSP promoter diminishes TET3 recruitment and demethylation, downregulating desmoplakin and impairing keratinocyte MET and re-epithelialization.

Key Findings

• Re-epithelialization failure in diabetic wounds is linked to impaired MET of keratinocytes rather than EMT.
• Desmoplakin (DSP) is downregulated due to reduced TET3 occupancy and diminished TET3-dependent demethylation at the DSP promoter.
• lncRNA DSP-AS1 forms R-loops at the DSP promoter to recruit TET3; its downregulation in diabetic skin reduces R-loops and suppresses DSP transcription.

Clinical Implications

Therapeutically augmenting DSP-AS1 function, stabilizing R-loops at the DSP promoter, or enhancing TET3 recruitment may accelerate re-epithelialization in refractory diabetic wounds.

Limitations

• Predominantly preclinical with species-specific differences likely; human tissue validation scope is limited in the abstract.
• Therapeutic modulation of R-loops/TET3 may carry off-target genomic risks requiring careful safety evaluation.

Future Directions

Validate DSP-AS1/TET3/R-loop signatures in human diabetic ulcer biopsies; develop RNA therapeutics or epigenetic modulators to restore DSP expression and MET; assess safety of R-loop targeting.