TIP60, a key lysine acetyltransferase, acts as a wound-induced factor essential for efficient wound response in planaria

Chromatin modifiers are essential regulators of gene expression, DNA repair, replication and cell division. Among them, histone acetyl transferase such as TIP60 play a central role in modulating chromatin dynamics through acetylation of histone and non-histone proteins. TIP60, a member of MYST family of HATs, is known to regulate key cellular processes, including transcriptional activation, DNA damage response and cell cycle progression. Although TIP60 role in stem cell maintenance and differentiation is well established, its function in stem cell derived regeneration has remain unexplored. In this study we characterized the role of TIP60 homolog, SMED-TIP60, in the planaria Schmidtea mediterranea, a odel organism renowed for its regeneration capacity. Biochemical assays confirmed SMED-TIP60 acetyl transferase and autoacetylation activity. RNAi mediated knockdown of smed-tip60 resulted in severe defects in tissue homeostasis, survival and regeneration. In situ hybridization and immunoflourescence analysis revealed a marked reduction in stem cell population and mitotic activity. Western blotting showed a peak in SMED-TIP60 expression at 5 day post amputation, suggesting a role during regeneration. RNA-seq analysis revealed widespread dysregulation of gene expression at both anterior and posterior wounds, correlating with increased TIP60 expression post injury. Notably wound response gene expression was aberrant in smed-tip60 RNAi animals, indicating TIP60 essential role in initiating wound responses and resetting positional cues. Together, these findings establish TIP60 as a critical regulator of stem cell mediated regeneration and wound healing in planarians.