Dynamic bookmarking of primary response genes by p300 and RNA polymerase II complexes
Dynamic bookmarking of primary response genes by p300 and RNA polymerase II complexes
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DOI：
10.1073/pnas.0905469106
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发表时间：
2009-11-17
影响因子：
11.1
通讯作者：
Gardner, Kevin
中科院分区：
文献类型：
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作者：
Byun, Jung S.;Wong, Madeline M.;Gardner, Kevin
通过分析p300与人类T细胞近端启动子的动态相互作用，发现了一类在有丝分裂原刺激后快速聚集p300和RNA聚合酶II （pol II）的基因。这些p300靶点中有几个是直接早期基因，包括FOS，这意味着p300在控制原发性遗传反应中起着重要作用。p300和pol II的募集迅速过渡到几个伸长因子的组装，包括正转录伸长因子（P-TEFb）、含溴结构域蛋白（BRD4）和长链样11 - 19赖氨酸丰富白血病蛋白（ELL）。然而，许多这些快速诱导基因的转录是短暂的，其中P-TEFb， BRD4和ELL的快速离开与转录延伸的终止一致。出乎意料的是，在转录终止后很长一段时间内，p300和pol II都在近端启动子上积累或“书签化”，这标志着体内转录的募集期和延伸期之间存在明显的机制分离。标记的pol II在其c端结构域的丝氨酸-2和丝氨酸-5磷酸化都被耗尽，并且在启动子的近端位置保持数小时。令人惊讶的是，这些p300/pol II书签标记的基因可以很容易地重新激活，并且延伸因子可以通过随后添加非有丝分裂剂来重新组装，这些非有丝分裂剂单独在缺乏有丝分裂原刺激的预先预处理的情况下对转录的影响很小。这些发现表明，p300可能在转录书签或预处理影响细胞生长和发育的生物过程中发挥重要作用，通过基因的动态启动来应对二次刺激的再挑战。
Profiling the dynamic interaction of p300 with proximal promoters of human T cells identified a class of genes that rapidly coassemble p300 and RNA polymerase II (pol II) following mitogen stimulation. Several of these p300 targets are immediate early genes, including FOS, implicating a prominent role for p300 in the control of primary genetic responses. The recruitment of p300 and pol II rapidly transitions to the assembly of several elongation factors, including the positive transcriptional elongation factor (P-TEFb), the bromo-domain-containing protein (BRD4), and the elongin-like eleven nineteen lysine-rich leukemia protein (ELL). However, transcription at many of these rapidly induced genes is transient, wherein swift departure of P-TEFb, BRD4, and ELL coincides with termination of transcriptional elongation. Unexpectedly, both p300 and pol II remain accumulated or "bookmarked'' at the proximal promoter long after transcription has terminated, demarking a clear mechanistic separation between the recruitment and elongation phases of transcription in vivo. The bookmarked pol II is depleted of both serine-2 and serine-5 phosphorylation of its C-terminal domain and remains proximally positioned at the promoter for hours. Surprisingly, these p300/pol II bookmarked genes can be readily reactivated, and elongation factors can be reassembled by subsequent addition of nonmitogenic agents that, alone, have minimal effects on transcription in the absence of prior preconditioning by mitogen stimulation. These findings suggest that p300 is likely to play an important role in biological processes in which transcriptional bookmarking or preconditioning influences cellular growth and development through the dynamic priming of genes for response to rechallenge by secondary stimuli.