Apoptosis in human myelodysplastic syndrome CD34+ cells is modulated by the upregulation of TLRs and histone H4 acetylation via a β-arrestin 1 dependent mechanism.
Apoptosis in human myelodysplastic syndrome CD34+ cells is modulated by the upregulation of TLRs and histone H4 acetylation via a β-arrestin 1 dependent mechanism.
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DOI：
10.1016/j.yexcr.2015.12.008
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发表时间：
2016
影响因子：
3.7
通讯作者：
Qing Zeng;Jing Shu;Q. Hu;Shao-hong Zhou;Y. Qian;Ming-hui Hu;Ling-yan Hu;Yu-Guang Wang;Yong-ming Zhou;Jia-hui Lu
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文献类型：
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作者：
Qing Zeng;Jing Shu;Q. Hu;Shao-hong Zhou;Y. Qian;Ming-hui Hu;Ling-yan Hu;Yu-Guang Wang;Yong-ming Zhou;Jia-hui Lu
骨髓中造血祖细胞的过度凋亡是骨髓增生异常综合征(MDS)无效造血特征的基础。Toll样受体(Toll-like Receptor，TLR)信号在MDS中异常激活，可能参与MDS的细胞过度程序性死亡。检测20例低危MDS患者、20例高危MDS患者和10例健康对照骨髓CD34+细胞TLRs表达和组蛋白H3/H4乙酰化水平。用流式细胞仪检测BMCD34+细胞的凋亡率，并用酶联免疫吸附试验和定量RT-PCR法检测其与组蛋白乙酰化、TLR2和β-arr1(β-ARR1)表达的相关性。低危MDS患者TLR1、TLR2和TLR6表达及H4乙酰化水平均高于高危MDS患者或对照组，且TLR2表达和H4乙酰化水平与细胞凋亡率呈正相关。低风险MDS与β-ARR1表达和组蛋白乙酰转移酶p300活性增加有关。在体外培养的原代正常和低危MDS CD34+细胞中，TLR2激活通过上调β-Arr1导致p300募集和组蛋白H4乙酰化增加而诱导细胞凋亡。TLR2激活后βarr1的核聚集促进了特定靶基因启动子上的H4乙酰化，从而可能影响BM CD34+细胞中靶基因的转录。β-Arr1介导的p300募集导致组蛋白H4乙酰化水平升高可能是MDS中TLR2表达下调和细胞凋亡率增加的机制之一。
Excessive apoptosis of hematopoietic precursors in the bone marrow underlies the ineffective hematopoiesis characteristic of myelodysplastic syndrome (MDS). Toll-like receptor (TLR) signaling is abnormally activated in MDS and may be involved in excessive programmed cell death in the pathogenesis of MDS. TLRs expression and global histone H3/H4 acetylation were analyzed in bone marrow (BM) CD34+ cells from 20 lower-risk and 20 higher-risk MDS patients and 10 healthy controls. Apoptosis of BM CD34+ cells was examined by flow cytometry, and its correlation to histone acetylation and the expression of TLR2 and β-arrestin1 (β-arr1), measured by enzyme-linkedimmunosorbent assay and qRT-PCR, was assessed. TLR1, TLR2 and TLR6 expression and H4 acetylation levels were higher in lower-risk MDS patients than in higher-risk MDS patients or controls, and TLR2 expression and H4 acetylation levels were positively correlated with an increased rate of apoptosis. Lower-risk MDS was associated with increased β-arr1 expression and histone acetyltransferase p300 activity. Inin vitro-cultured primary normal and lower-risk MDS CD34+ cells, TLR2 activation-induced apoptosis was mediated by the upregulation of β-arr1 leading to the recruitment of p300 and increased histone H4 acetylation. The nuclear accumulation of βarr1 following TLR2 activation promote H4 acetylation at specific target gene promoters and may thus affect transcription of target genes in BM CD34+ cells. The mechanisms underlying the deregulation of TLR2 and increased apoptosis in MDS may involve the β-arr1 mediated recruitment of p300 leading to increased levels of histone H4 acetylation.