抗氧化機制可以維持活性氧 (ROS) 的動態平衡，當活性氧數量超越抗氧化機制所能負荷的程度時，將對細胞造成傷害。先前文獻指出，提升抗氧化基因的表達量，可以有效抑制過量活性氧所造成的氧化壓力，進而達到保護模式生物與延長壽命之效果。有趣的是，提升調控異染色質形成的異染色質蛋白質1 (Heterochromatin protein 1, HP1) 的表現量，在果蠅中亦觀察到具有促進長壽的效果。然而，其相關分子機制並不完全清楚。因此本研究利用表現不同程度異染色質蛋白質1的果蠅當作模式生物，並製造過量的氧化壓力，藉由計算果蠅的存活率，來探討異染色質是否透過表觀遺傳學調控抗氧化機制。實驗結果顯示，提高異染色質蛋白質1表現量的果蠅，對於氧化壓力具有較佳的抵抗能力；相反地，降低異染色質蛋白質1表現量的果蠅，面臨氧化壓力時較容易死亡。除此之外，亦觀察到提高異染色質蛋白質1表現量，可以降低內源性活性氧的量。更進一步，我們比對果蠅模式生物的基因資料庫，找出七個抗氧化基因能受到異染色質蛋白質1的調控，其中已知磷酸核糖異構酶 (Rpi) 參與氧化壓力與壽命的調控。綜合以上結果，我們推測：異染色質調控抗氧化相關基因的表達量來扮演保護的角色，以維持活性氧的動態恆定。而未來仍需進一度探討，異染色質蛋白質1促進抗氧化壓力是否能藉由表觀遺傳直接地調控抗氧化相關基因。因此，本研究能提供對於老化相關疾病預防和治療的新方向，希望可以促進人類健康與長壽。

Cellular damage occurs when excessive reactive oxidative species (ROS) overwhelms the cell’s antioxidant defense mechanisms that normally help maintain ROS oxidative homeostasis. Previous studies demonstrated that overexpression of antioxidant genes, suppressing excessive ROS levels, is protective and extends the lifespan in model organisms. Interestingly, the formation of heterochromatin, a compacted form of chromatin, is mediated by heterochromatin protein 1 (HP1) and epigenetically enhances longevity in Drosophila. However, the molecular and cellular mechanisms by which heterochromatin promotes longevity remain elusive. In this study, we determined whether heterochromatin regulates the antioxidant defense system via epigenetic mechanisms in Drosophila. We examined the survival of animals with different levels of HP1 under oxidative stress. We found that animals with increased levels of heterochromatin confer resistance to oxidative stress, and conversely, animals with reduced levels of heterochromatin are more susceptible to ROS-induced lethality. Moreover, we also observed that increased heterochromatin levels decreases endogenous ROS levels. By analyzing antioxidant gene expression microarray and qRT-PCR studies, we verified seven putative HP1-regulated antioxidant-related genes, including ribose-5-phosphate isomerase (rpi), which has been shown to regulate oxidative resistance and lifespan in Drosophila. Taken together, these results suggest that heterochromatin regulates antioxidant-related genes and plays a protective role in maintaining ROS homeostasis in response to oxidative stress. Further studies are necessary to determine whether HP1 promotes oxidative resistance by reducing ROS levels through direct epigenetic modulation of these antioxidant-related genes. This study may provide new preventive/therapeutic treatments for age-dependent diseases and pave the way for improvement in human health- and life-span.

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