Heritable transmission of diabetic metabolic memory in zebrafish correlates with DNA hypomethylation and aberrant gene expression.
Heritable transmission of diabetic metabolic memory in zebrafish correlates with DNA hypomethylation and aberrant gene expression.
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作者：
Olsen AS;Sarras MP Jr;Leontovich A;Intine RV
代谢记忆是指糖尿病并发症持续存在并在血糖恢复后进展的现象。在这里，我们提供的数据表明多发性骨髓瘤是可遗传的，这种传递与高血糖诱导的DNA低甲基化和基因表达异常有关。链佐菌素被用来诱导成年斑马鱼的高血糖，然后，在停用链佐菌素后，允许恢复期重新建立正常血糖状态。由于胰腺β细胞的再生，血糖和血清胰岛素在恢复期的前两周恢复到生理水平。相比之下，尾鳍再生和皮肤伤口愈合仍然受到与糖尿病鱼相同程度的损害，这种损害可传递到子代细胞组织。从未接触过高血糖的子代组织，但从组织中提取的子代组织不积累AGE或表现出更高的氧化应激水平。然而，CpG岛甲基化和全基因组微阵列表达分析显示，高血糖诱导的全球DNA低甲基化持续存在，这与该子组织中一组基因座的异常基因表达有关。总而言之，这里提供的数据暗示了DNA甲基化的表观遗传机制是MM现象的潜在贡献者。
Metabolic memory (MM) is the phenomenon whereby diabetes complications persist and progress after glycemic recovery is achieved. Here, we present data showing that MM is heritable and that the transmission correlates with hyperglycemia-induced DNA hypomethylation and aberrant gene expression. Streptozocin was used to induce hyperglycemia in adult zebrafish, and then, following streptozocin withdrawal, a recovery phase was allowed to reestablish a euglycemic state. Blood glucose and serum insulin returned to physiological levels during the first 2 weeks of the recovery phase as a result of pancreatic β-cell regeneration. In contrast, caudal fin regeneration and skin wound healing remained impaired to the same extent as in diabetic fish, and this impairment was transmissible to daughter cell tissue. Daughter tissue that was never exposed to hyperglycemia, but was derived from tissue that was, did not accumulate AGEs or exhibit increased levels of oxidative stress. However, CpG island methylation and genome-wide microarray expression analyses revealed the persistence of hyperglycemia-induced global DNA hypomethylation that correlated with aberrant gene expression for a subset of loci in this daughter tissue. Collectively, the data presented here implicate the epigenetic mechanism of DNA methylation as a potential contributor to the MM phenomenon.
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