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The crucial role of SETDB1 in structural and functional transformation of epithelial cells during regeneration after intestinal ischemia reperfusion injury

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Su (var) 3–9, enhancer of seste, trithorax (SET)-domain bifurcated histone lysine methyltransferase (SETDB1) plays a crucial role in maintaining intestinal stem cell homeostasis; however, its physiological function in epithelial injury is largely unknown. In this study, we investigated the role of SETDB1 in epithelial regeneration using an intestinal ischemia/reperfusion injury (IRI) mouse model. Jejunum tissues were sampled after 75 min of ischemia followed by 3, 24, and 48 h of reperfusion. Morphological evaluations were performed using light microscopy and electron microscopy, and the involvement of SETDB1 in epithelial remodeling was investigated by immunohistochemistry. Expression of SETDB1 was increased following 24 h of reperfusion and localized in not only the crypt bottom but also in the transit amplifying zone and part of the villi. Changes in cell lineage, repression of cell adhesion molecule expression, and decreased histone H3 methylation status were detected in the crypts at the same time. Electron microscopy also revealed aberrant alignment of crypt nuclei and fusion of adjacent villi. Furthermore, increased SETDB1 expression and epithelial remodeling were confirmed with loss of stem cells, suggesting SETDB1 affects epithelial cell plasticity. In addition, crypt elongation and increased numbers of Ki-67 positive cells indicated active cell proliferation after IRI; however, the expression of PCNA was decreased compared to sham mouse jejunum. These morphological changes and the aberrant expression of proliferation markers were prevented by sinefungin, a histone methyltransferase inhibitor. In summary, SETDB1 plays a crucial role in changes in the epithelial structure after IRI-induced stem cell loss.

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This study was supported in part by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (no. 21K06738 to Y. Hishikawa), and Grant for Clinical Research from Miyazaki University Hospital (M. Ikenoue). We gratefully acknowledge the Frontier Science Research Center at the University of Miyazaki for allowing us to use their facilities.

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MI, YH designed all experiments, MI, NC, YH wrote the manuscript, MI, NC, KY, NT, SS, YY performed experiments, MI, NC, AS, YH analyzed data, and TI, KK, KH, F, AN provided mouse, reagents and information.

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Correspondence to Yoshitaka Hishikawa.

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Ikenoue, M., Choijookhuu, N., Yano, K. et al. The crucial role of SETDB1 in structural and functional transformation of epithelial cells during regeneration after intestinal ischemia reperfusion injury. Histochem Cell Biol 161, 325–336 (2024).

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