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首页> 外文期刊>International journal of molecular medicine >ExpresPlastrum testudinis induces γ-globin gene expression through epigenetic histone modifications within the γ-globin gene promoter via activation of the p38 MAPK signaling pathway
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ExpresPlastrum testudinis induces γ-globin gene expression through epigenetic histone modifications within the γ-globin gene promoter via activation of the p38 MAPK signaling pathway

机译：ExpresPlastrum testudinis通过激活p38 MAPK信号通路通过γ-珠蛋白基因启动子内的表观遗传组蛋白修饰诱导γ-珠蛋白基因表达

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摘要

The pharmacologically-induced expression of the γ-globin gene, to increase fetal hemoglobin (HbF) production, is a therapeutic strategy used for the treatment of β-thalassemia and sickle cell anemia (SCA). The aim of this study was to investigate the effects of Plastrum testudinis (PT) on differentiation, proliferation, γ-globin gene expression and HbF synthesis in human erythroid cells. For this purpose, we used the K562 human leukemia cell line and human erythroid progenitor cells from normal donors and patients with β-thalassemia cultured using the two-phase liquid culture system. The effects of PT on erythroid differentiation, proliferation, γ-globin gene expression and HbF synthesis, as well as the involvement of epigenetic histone modifications within the γ-globin gene promoter via activation of the p38 mitogen-activated protein kinase (MAPK) signaling pathway, were assessed by benzidine staining, trypan-blue dye exclusion, quantitative real-time RT-PCR (qRT-PCR), western blot analysis and chromatin immunoprecipitation (ChIP). PT promoted the erythroid differentiation of K562 cells, and increased γ-globin mRNA accumulation and HbF synthesis without inhibiting cell proliferation in K562 cells and human erythroid progenitors. PT exerted no effect on and β-globin gene expression. In human erythroid cells, PT activated the p38 MAPK signaling pathway, and enhanced the acetylation of histone H3 and H4, the phosphorylation of histone H3 within the Gγ-and Aγ-globin gene promoter regions, γ-globin mRNA accumulation and HbF synthesis. These effects were suppressed by pre-treatment with the p38 MAPK inhibitor, SB203580. Epigenetic histone modifications within γ-globin gene promoter regions, via activation of the p38 MAPK signaling pathway, are important for the induction of γ-globin gene expression in human erythroid cells by PT. PT may be a novel potential therapeutic agent for β-hemoglobinopathies, including β-thalassemia and SCA.
机译：药理学诱导的γ-珠蛋白基因表达，以增加胎儿血红蛋白（HbF）的产生，是用于治疗β地中海贫血和镰状细胞性贫血（SCA）的治疗策略。这项研究的目的是调查对人体红细胞中的Plastrum睾丸（PT）的分化，增殖，γ珠蛋白基因表达和HbF合成的影响。为了这个目的，我们使用了来自正常供体和通过两相液体培养系统培养的β地中海贫血患者的K562人白血病细胞系和人红系祖细胞。 PT对红细胞分化，增殖，γ-珠蛋白基因表达和HbF合成的影响，以及通过激活p38丝裂原激活的蛋白激酶（MAPK）信号通路而在γ-珠蛋白基因启动子中参与表观遗传组蛋白修饰的影响通过联苯胺染色，锥虫蓝染料排除，定量实时RT-PCR（qRT-PCR），蛋白质印迹分析和染色质免疫沉淀（ChIP）进行评估。 PT促进K562细胞的红系分化，并在不抑制K562细胞和人类红系祖细胞增殖的情况下增加γ-珠蛋白mRNA的积累和HbF合成。 PT对β-珠蛋白基因表达无影响。在人红系细胞中，PT激活了p38 MAPK信号通路，并增强了组蛋白H3和H4的乙酰化，增强了Gγ和Aγ珠蛋白基因启动子区域内组蛋白H3的磷酸化，γ珠蛋白mRNA的积累和HbF的合成。通过用p38 MAPK抑制剂SB203580进行预处理可以抑制这些作用。 γ-珠蛋白基因启动子区域内的表观遗传组蛋白修饰，通过激活p38 MAPK信号通路，对PT诱导人红细胞中γ-珠蛋白基因表达很重要。 PT可能是β-血红蛋白病（包括β-地中海贫血和SCA）的新型潜在治疗剂。

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