Mill1 基因甲基化异常调控成骨分化,涉及大鼠骨骼氟中毒的各种表型和蛋氨酸干预。

IF 6.2 2区 环境科学与生态学 Q1 ENVIRONMENTAL SCIENCES
Niannian Chen, Jing Zhang, Congyu Yin, Yudan Liao, Lei Song, Ting Hu, Xueli Pan
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引用次数: 0

摘要

氟摄入过多会导致骨骼氟中毒。在相同的氟暴露环境中,营养差异会导致骨硬化、骨质疏松症和骨软化症。研究发现,DNA甲基化与骨骼氟中毒有关,并受环境和营养的影响。在之前的一项研究中,我们筛选了与骨骼氟中毒各种表型相关的八个甲基化差异基因。结合基因功能,我们选择了 Mill1 基因进行后续实验。首先,我们发现 Mill1 基因在骨硬化性骨骼氟中毒中呈低甲基化和上调,而在骨质疏松症/骨软化症骨骼氟中毒中呈高甲基化和下调。细胞实验也得到了类似的结果。随后,我们利用 DNMT1 和 TET2 酶抑制剂验证了 Mill1 基因甲基化的调控作用。此外,我们还通过敲除和过表达实验证实,下调 Mill1 基因会抑制成骨分化,而过表达 Mill1 基因则会促进成骨分化。这些发现意味着,在不同的营养条件下,氟引发了 Mill1 基因的异常甲基化,调节了其表达并参与了成骨分化,从而可能导致骨骼氟中毒的各种表型。最终,我们利用蛋氨酸在体内和体外进行干预。结果表明,在正常营养和氟暴露条件下,蛋氨酸干预后,Mill1 基因的甲基化水平升高,而其高表达和成骨分化的增强却受到抑制。这项研究为从DNA甲基化的角度理解骨骼氟中毒各种表型背后的机制,以及利用营养素干预骨骼氟中毒提供了理论基础。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Abnormal methylation of Mill1 gene regulates osteogenic differentiation involved in various phenotypes of skeletal fluorosis in rats and methionine intervention.

Excessive fluoride intake can lead to skeletal fluorosis. Nutritional differences in the same fluoride-exposed environment result in osteosclerosis, osteoporosis, and osteomalacia. DNA methylation has been found to be involved in skeletal fluorosis and is influenced by environment and nutrition. In a previous study, we screened eight genes with differential methylation associated with various phenotypes of skeletal fluorosis. By combining gene functions, Mill1 gene was selected for subsequent experiments. First, we found that the Mill1 gene was hypomethylated and upregulated in osteosclerosis skeletal fluorosis, whereas it was hypermethylated and downregulated in osteoporosis/osteomalacia skeletal fluorosis. Similar results were obtained in the cell experiments. Subsequently, we validated the regulation of Mill1 gene methylation using DNMT1 and TET2 enzyme inhibitors. Furthermore, we knockdown and overexpression experiments confirmed its downregulation inhibited osteogenic differentiation, whereas osteogenic differentiation was promoted by its overexpression. These findings imply that abnormal methylation of the Mill1 gene triggered by fluoride under diverse nutritional conditions, regulates its expression and participates in osteogenic differentiation, potentially resulting in various phenotypes of skeletal fluorosis. Eventually, we use methionine for interventions both in vivo and in vitro. The results indicated that under normal nutrition and fluoride exposure followed by methionine intervention, the methylation levels of the Mill1 gene increased, whereas its high expression and enhanced osteogenic differentiation were restrained. This study offers a theoretical foundation for understanding the mechanism behind the various phenotypes of skeletal fluorosis through the perspective of DNA methylation and for employing nutrients to intervene in skeletal fluorosis.

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来源期刊
CiteScore
12.10
自引率
5.90%
发文量
1234
审稿时长
88 days
期刊介绍: Ecotoxicology and Environmental Safety is a multi-disciplinary journal that focuses on understanding the exposure and effects of environmental contamination on organisms including human health. The scope of the journal covers three main themes. The topics within these themes, indicated below, include (but are not limited to) the following: Ecotoxicology、Environmental Chemistry、Environmental Safety etc.
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