METTL3-Mediated m6A RNA Modification Regulates Corneal Injury Repair

Abstract

Limbal stem cells are essential for continuous corneal regeneration and injury repair. METTL3-catalyzed N6-methyladenosine (m6A) mRNA modifications are involved in many biological processes and play a specific role in stem cell regeneration, while the role of m6A modifications in corneal injury repair remains unknown. In this study, we generated a limbal stem cell-specific METTL3 knockout mouse model and studied the role of m6A in repairing corneal injury caused by alkali burn. The results showed that METTL3 knockout in the limbal stem cells promotes the in vivo cell proliferation and migration, leading to the fast repair of corneal injury. In addition, m6A modification profiling identified stem cell regulatory factors AHNAK and DDIT4 as m6A targets. Our study reveals the essential functions of m6A RNA modification in regulating injury repair and provides novel insights for clinical therapy of corneal diseases.

Alteration of m6A epitranscriptomic tagging of ribonucleic acids after spinal cord injury in mice

“…Our previous study demonstrated that the epigenetic network is essential for vascular regeneration and functional recovery post-SCI ( Ni et al, 2019 ). The m 6 A methylation plays a significant role in the pathological process of corneal injury, brain injury, and peripheral nerve injury ( Weng et al, 2018 ; Wang et al, 2019 ; Dai et al, 2021 ; Zhang et al, 2021 ). In contrast, various types of cancers and diabetes are associated with lowered m 6 A abundance ( Chen et al, 2020 ; Huang et al, 2021 ; Lei et al, 2021 ; Ruan et al, 2021 ; Wang et al, 2021a ; Ye et al, 2021 ).…”

Methylation in cornea and corneal diseases: a systematic review

“…Moreover, the involvement of these genes suggests that they may play a role in regulating WNT signaling [ 134 ]. Additionally, knocking out METTL3 in corneal limbal stem cells promotes the proliferation and migration of in vivo cells, resulting in fast repair of corneal injury [ 135 , 136 ]. During corneal injury, CECs also migrate more rapidly.…”

“…Corneal limbal stem cells possess the ability to regularly renew and differentiate, and they migrate to the central cornea to replace damaged or dead CECs [ 137 ]. This research highlight the crucial role of m 6 A in regulating corneal injury repair and offers new insights for the treatment of CDs [ 136 ].…”

Recent progress in N6-methyladenosine modification in ocular surface diseases

“…In the acute phase of alkaline injuries, over 50% of corneal limbal ischemia is an influential contributor to the dysfunction of the limbal stem cells [60] . Dai et al [61] created a limbal stem cell-specific METTL3 knockout (cKO) mouse model and investigated the function of m6A in repairing corneal injury after alkali burns. On days 7 and 14 after alkali burns, the METTL3 cKO mice had more complete corneal epithelium and less stromal layer neovascularization compared to wildtype mice, suggesting that METTL3 knockdown inhibited pathological vascularization and promoted corneal injury repair.…”