Epigenetically rewiring metabolic genes via SIRT6 orchestrates MSC fate determination

作者：Xueyang Liao, Feifei Li, Fanyuan Yu, Ling Ye · 发表于：Stem Cells · 年份：2024 · DOI：10.1093/stmcls/sxae041 · 被引用次数：3 · 研究领域：Sirtuins and Resveratrol in Medicine、Autophagy in Disease and Therapy、CRISPR and Genetic Engineering

SIRT6 owns versatile types of enzymatic activities as a multitasking protein, including ribosyltransferase and deacetylase. To investigate the epigenetic regulations of SIRT6 on MSC fate determination via histone deacetylation, we used allosteric small molecules specifically controlling its histone 3 deacetylation activities. Results showed that enhanced deacetylation of SIRT6 promoted the ossific lineage commitment of MSC and finally achieved anabolic effects on hard tissues. Mechanistically, H3K9ac and H3K56ac, governed by SIRT6, in MSC orchestrated the transcriptions of crucial metabolic genes, mediating MSC fate determination. Most importantly, our data evidenced that modulating the epigenetic regulations of SIRT6, specifically via enhancing its deacetylation of H3K9ac and H3K56ac, was a promising choice to treat bone loss diseases and promote dentin regeneration. In this study, we revealed the specific roles of SIRT6's histone modification in MSC fate determination. These findings endow us with insights on SIRT6 and the promising therapeutic choices through SIRT6's epigenetic functions for hard tissues regeneration.