Mass Spectrometric Studies on Epigenetic Interaction Networks in Cell Differentiation
Mass Spectrometric Studies on Epigenetic Interaction Networks in Cell Differentiation
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DOI：
10.1074/jbc.m110.204800
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发表时间：
2011-04-15
影响因子：
4.8
通讯作者：
Zhang, Kangling
中科院分区：
文献类型：
--
作者：
Xiong, Lei;Darwanto, Agus;Zhang, Kangling
细胞分化停滞是白血病和其他癌症的主要原因之一。临床上已经尝试使用药剂诱导细胞分化来治疗这些癌症。表观遗传调控可能是控制细胞增殖或分化的潜在分子机制之一。在这里，我们报告使用蛋白质组学为基础的差异蛋白表达分析结合组蛋白修饰的量化来破译表观遗传修饰，其修饰酶或介质之间的相互联系，以及在细胞分化过程中发生的相关途径/网络的变化。在佛波醇12-肉豆蔻酸酯13-乙酸酯诱导U937细胞分化过程中，脂肪酸合成及其代谢过程、网格蛋白包被的小凹内吞途径和泛素/26 S蛋白酶体降解途径均上调。此外，全球组蛋白H3/H4乙酰化和H2 B泛素化下调伴随着受损的染色质重塑机制，RNA聚合酶II复合物，和DNA复制。差异蛋白表达分析建立了将组蛋白低乙酰化与下调的p300表达/活性联系起来的网络，并将组蛋白H2 B泛素化与RNA聚合酶II相关的FACT-RTF 1-PAF 1复合物联系起来。总的来说，我们的方法为表观遗传调控在白血病细胞分化中的作用提供了前所未有的系统性见解。
Arrest of cell differentiation is one of the leading causes of leukemia and other cancers. Induction of cell differentiation using pharmaceutical agents has been clinically attempted for the treatment of these cancers. Epigenetic regulation may be one of the underlying molecular mechanisms controlling cell proliferation or differentiation. Here, we report on the use of proteomics-based differential protein expression analysis in conjunction with quantification of histone modifications to decipher the interconnections among epigenetic modifications, their modifying enzymes or mediators, and changes in the associated pathways/networks that occur during cell differentiation. During phorbol-12-myristate 13-acetate-induced differentiation of U937 cells, fatty acid synthesis and its metabolic processing, the clathrin-coated pit endocytosis pathway, and the ubiquitin/26 S proteasome degradation pathways were up-regulated. In addition, global histone H3/H4 acetylation and H2B ubiquitination were down-regulated concomitantly with impaired chromatin remodeling machinery, RNA polymerase II complexes, and DNA replication. Differential protein expression analysis established the networks linking histone hypoacetylation to the down-regulated expression/activity of p300 and linking histone H2B ubiquitination to the RNA polymerase II-associated FACT-RTF1-PAF1 complex. Collectively, our approach has provided an unprecedentedly systemic set of insights into the role of epigenetic regulation in leukemia cell differentiation.