Analysis of Myc-induced histone modifications on target chromatin.
Analysis of Myc-induced histone modifications on target chromatin.
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DOI：
10.1371/journal.pone.0003650
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发表时间：
2008
期刊：
影响因子：
3.7
通讯作者：
Guccione E
中科院分区：
文献类型：
--
作者：
Martinato F;Cesaroni M;Amati B;Guccione E
c-myc原癌基因由有丝分裂原诱导，是细胞生长和分化的中心调节因子。c-myc产物Myc是一种转录因子，其结合大量基因组位点，估计超过所有启动子区域的10-15%。靶启动子通常预先存在于由Myc进一步修饰的活性或平衡的染色质状态中，有助于传入基因的精细转录调节（激活或抑制）。在其他机制中，Myc招募组蛋白乙酰转移酶靶向染色质，并局部促进组蛋白H3和H4上多个赖氨酸的超乙酰化，尽管修饰的赖氨酸的身份和组合是未知的。Myc是否动态调节其结合位点的其他组蛋白修饰（或标记）也仍有待解决。在这里，我们使用定量染色质免疫沉淀法（qChIP）来分析共24个赖氨酸乙酰化和甲基化标记调制的Myc在目标启动子在人类B细胞系与可调控的c-myc转基因。Myc结合促进多个赖氨酸的乙酰化，主要是H3 K9、H3 K14、H3 K18、H4 K5和H4 K12的乙酰化，但也显著促进H4 K8、H4 K91和H2 AK 5的乙酰化。在靶启动子处也选择性地诱导H3 K79的二甲基化。大多数靶启动子显示多种标记的共诱导-以各种组合-与测试的两种HAT（Tip 60和HB 0 1）的募集、组蛋白变体H2A.Z的掺入和转录激活相关。基于这一点和以前的研究结果，我们推测Myc招募Tip 60/p400复合物，以实现在激活的启动子协调组蛋白乙酰化/交换反应。我们的数据也与多乙酰化事件在转录激活中的附加和冗余作用一致。
The c-myc proto-oncogene is induced by mitogens and is a central regulator of cell growth and differentiation. The c-myc product, Myc, is a transcription factor that binds a multitude of genomic sites, estimated to be over 10–15% of all promoter regions. Target promoters generally pre-exist in an active or poised chromatin state that is further modified by Myc, contributing to fine transcriptional regulation (activation or repression) of the afferent gene. Among other mechanisms, Myc recruits histone acetyl-transferases to target chromatin and locally promotes hyper-acetylation of multiple lysines on histones H3 and H4, although the identity and combination of the modified lysines is unknown. Whether Myc dynamically regulates other histone modifications (or marks) at its binding sites also remains to be addressed. Here, we used quantitative chromatin immunoprecipitation (qChIP) to profile a total of 24 lysine-acetylation and -methylation marks modulated by Myc at target promoters in a human B-cell line with a regulatable c-myc transgene. Myc binding promoted acetylation of multiple lysines, primarily of H3K9, H3K14, H3K18, H4K5 and H4K12, but significantly also of H4K8, H4K91 and H2AK5. Dimethylation of H3K79 was also selectively induced at target promoters. A majority of target promoters showed co-induction of multiple marks - in various combinations - correlating with recruitment of the two HATs tested (Tip60 and HBO1), incorporation of the histone variant H2A.Z and transcriptional activation. Based on this and previous findings, we surmise that Myc recruits the Tip60/p400 complex to achieve a coordinated histone acetylation/exchange reaction at activated promoters. Our data are also consistent with the additive and redundant role of multiple acetylation events in transcriptional activation.
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