Impairment of human terminal erythroid differentiation by histone deacetylase 5 deficiency
Impairment of human terminal erythroid differentiation by histone deacetylase 5 deficiency
复制标题
组蛋白脱乙酰酶 5 缺陷导致人类终末红细胞分化受损。
DOI：
10.1182/blood.2020007401
复制
发表时间：
2021
期刊：
影响因子：
20.3
通讯作者：
Xiuli An
中科院分区：
文献类型：
--
作者：
Yaomei wang;Wei Li;Vincent P. Schulz;Huizhi Zhao;Xiaoli Qu;Qian Qi;Yong Cheng;Xinhua Guo;Shijie Zhang;Xin Wei;Donghao Liu;Karina Yazdanbakhsh;Christopher D Hillyer;Narla Moh;as;Lixiang Chen;Patrick G. Gallagher;Xiuli An
组蛋白去乙酰化酶（HDACs）是一类催化从组蛋白和非组蛋白蛋白质上去除乙酰基的酶。已有研究表明，HDACs在广泛的生物学过程中发挥着多种功能。然而，它们在哺乳动物红细胞生成中的作用仍有待全面阐明。我们在此表明，在11个经典的HDAC家族成员中，有6个（HDAC 1、2、3以及HDAC 5、6、7）在人类红系细胞中表达，其中HDAC5在终末红系分化过程中上调最为显著。在人类CD34 +细胞中通过短发夹RNA（shRNA）或小干扰RNA（siRNA）敲低HDAC5，随后进行红系细胞培养，结果导致细胞凋亡增加、染色质凝聚减少以及成红细胞去核受损。生化分析显示，HDAC5缺失导致p53激活，同时p53的乙酰化增加。此外，虽然在正常终末红系分化过程中组蛋白4（H4）的乙酰化减少，但HDAC5缺失导致晚期成红细胞中H4（K12）的乙酰化增加。这种乙酰化增加伴随着染色质凝聚减少，这意味着H4（K12）去乙酰化在染色质凝聚中发挥作用。转座酶可及染色质测序（ATAC - seq）和RNA测序（RNA - seq）分析表明，HDAC5敲低导致全基因组染色质可及性增加以及基因表达的全局性变化。此外，用抑制剂LMK235对HDAC5进行药理学抑制也导致H4乙酰化增加、染色质凝聚和去核受损。综上所述，我们的研究结果揭示了HDAC5在人类红细胞生成中此前未被认识到的作用和分子作用机制。这些结果可能为理解与HDAC抑制剂治疗相关的贫血提供思路。
Histone deacetylases (HDACs) are a group of enzymes catalyzing the removal of acetyl groups from histone and non-histone proteins. HDACs have been shown to play diverse functions in a wide range of biological processes. However, their roles in mammalian erythropoiesis remain to be fully defined. We show here that of the eleven classic HDAC family members, six of them (HDAC 1,2,3 and HDAC 5,6,7) are expressed in human erythroid cells with HDAC5 most significantly up regulated during terminal erythroid differentiation. Knockdown of HDAC5 by either shRNA or siRNA in human CD34+ cells followed by erythroid cell culture led to increased apoptosis, decreased chromatin condensation, and impaired enucleation of erythroblasts. Biochemical analyses revealed that HDAC5 deficiency resulted in activation of p53 in association with increased acetylation of p53. Furthermore, while acetylation of histone 4 (H4) is decreased during normal terminal erythroid differentiation, HDAC5 deficiency led to increased acetylation of H4 (K12) in late stage erythroblasts. This increased acetylation was accompanied by decreased chromatin condensation, implying a role for H4 (K12) deacetylation in chromatin condensation. ATAC-seq and RNA-seq analyses revealed that HDAC5 knockdown leads to increased chromatin accessibility genome wide and global changes in gene expression. Moreover, pharmacological inhibition of HDAC5 by the inhibitor LMK235 also led to increased H4 acetylation, impaired chromatin condensation and enucleation. Taken together, our findings have uncovered previously unrecognized roles and molecular mechanisms of action for HDAC5 in human erythropoiesis. These results may provide insights into understanding the anemia associated with HDAC inhibitor treatment.