库尔库米诺酸激活TET酶并增加白血病细胞中的DNA基甲基化和活性脱甲基化
Sridhar A Malkaram1, Suhila Sawesi2, Botao Peng3
1Department of Mathematics, Engineering & Computer Science, West Virginia State University, Institute, WV 25112, USA.
黄素及其模拟物二甲基黄素 (DMC) 激活TET酶,增加5-基甲基细胞素 (5hmC) 水平,并促进白血病细胞中的活性DNA脱甲基化. 这表明它有可能作为白血病的表观遗传疗法.
科学领域:
- 表观遗传学 在表观遗传学中,表观遗传学是指表观遗传学.
- 分子生物学分子生物学
- 癌症研究 癌症研究
背景情况:
- 库尔库米诺类药物,包括黄素和二甲氧黄素 (DMC),表现出各种药理性质.
- 这些化合物调节涉及DNA甲基化和基因素修饰的表观遗传酶.
- 库尔库米诺类药物对TET酶的影响,这对白血病中5-基甲基细胞因子 (5hmC) 调节至关重要,仍然在很大程度上未知.
研究的目的:
- 研究黄素和DMC对白血病细胞中TET酶异型的活性和表达的影响.
- 分析这些化合物对全球5hmC水平和分布的影响.
- 在单个CpG位点层面进行5hmC变化的全基因组评估.
主要方法:
- 氧化双硫酸盐测序被用来区分5-甲基细胞因和5hmC.
- 测量了TET酶活性和mRNA表达.
- 全球5hmC水平被量化.
- 在单个CpG分辨率下分析了全基因组5hmC分布.
主要成果:
- 黄素和DMC都显著增加了所有三种TET酶异型的活性和mRNA表达.
- 在用黄素和DMC治疗的白血病细胞中,全球5hmC水平升高.
- 全基因组分析揭示了药物诱导的5hmC增加和各种基因组区域的活性脱甲基化,包括促进体,CpG岛屿,外因子和内因子.
- 在数百个基因中,黄素和DMC调节了促进子5hmC和脱甲基化.
结论:
- 库尔库米诺类药物通过激活TET酶,作为活性脱甲基化剂.
- 这些发现为探索黄素与DNA低甲基化剂结合用于白血病治疗提供了科学基础.
- 这项研究突出了库尔库米诺酸在癌症治疗的表观遗传调制中的潜力.
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