m6A promotes planarian regeneration

Regeneration is the regrowth of damaged tissues or organs, a vital process in response to damages from primitive organisms to higher mammals. Planarian possesses active whole‐body regenerative capability owing to its vast reservoir of adult stem cells, neoblasts, providing an ideal model to delineate the underlying mechanisms for regeneration. RNA N6‐methyladenosine (m6A) modification participates in many biological processes, including stem cell self‐renewal and differentiation, in particular the regeneration of haematopoietic stem cells and axons. However, how m6A controls regeneration at the whole‐organism level remains largely unknown. Here, we demonstrate that the depletion of m6A methyltransferase regulatory subunit wtap abolishes planarian regeneration, potentially through regulating genes related to cell–cell communication and cell cycle. Single‐cell RNA‐seq (scRNA‐seq) analysis unveils that the wtap knockdown induces a unique type of neural progenitor‐like cells (NP‐like cells), characterized by specific expression of the cell–cell communication ligand grn. Intriguingly, the depletion of m6A‐modified transcripts grn, cdk9 or cdk7 partially rescues the defective regeneration of planarian caused by wtap knockdown. Overall, our study reveals an indispensable role of m6A modification in regulating whole‐organism regeneration. As depicted in our model, during planarian homeostasis, the expression level of grn is held at a moderate level to inhibit overgrowth, as equivalent to grn expression level before amputation at 0 hpa. Upon injury, m6A modification selectively targets several important gene transcripts, including grn for degradation, manifested as its reduced expression level after 6 hpa, as well as transcripts of cell cycle‐related genes including ccnt1, cdk7 and cdk9. m6A‐mediated downregulation of these genes, especially the grn, may halt the initial proliferation of the stem cell pool at the first stage of regeneration, which in turn promotes their differentiation process, including the differentiation of neoblasts to the progenitor cells and eventually to different tissue types. After wtap knockdown, grn transcript accumulates to form a unique cell cluster resulting in increased GRN secretion, which may lead to cell cycle dysregulation and the loss of neoblast differentiation and the failure of planarian regeneration.