Gcn5: The quintessential histone acetyltransferase
Gcn5: The quintessential histone acetyltransferase
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Gcn5：典型的组蛋白乙酰转移酶
DOI：
10.1016/j.bbagrm.2020.194658
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发表时间：
2021
期刊：
影响因子：
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通讯作者：
Weake, Vikki M.
中科院分区：
文献类型：
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作者：
Weake, Vikki M.
自从Jim Brownell和大卫Allis发现第一个核组蛋白乙酰转移酶Gcn 5以来，染色质作为基因表达调节因子的概念在过去的25年里几乎是所有真核转录研究的基础[1，2]。构成染色质结构单元的组蛋白限制了对底层DNA的访问，早在20世纪50年代和60年代，组蛋白的存在就明显抑制了RNA的合成。观察到组蛋白可以通过翻译后添加乙酰基或甲基进行化学修饰[3，4]，这导致了由Vincent Allfrey首先倡导的想法，即组蛋白乙酰化可以作为控制转录的开关[5]。在接下来的几十年中，多项体外研究支持组蛋白的乙酰化可以刺激染色质模板的转录的观点（在[6，7]中综述）。此外，组蛋白乙酰化与细胞内的活性转录明显相关[6，7]。然而，缺乏任何好的候选酶，可以添加（或去除）细胞核内组蛋白的乙酰基标记是理解组蛋白乙酰化如何控制基因表达的主要障碍。在[8]这期特刊中，Jim Brownell和大卫Allis描述了对这种细胞核组蛋白乙酰转移酶活性的深入研究，其成功是由于巧妙的生物化学方法结合使用未被重视的生物体，嗜热四膜虫，其以其特化的转录活性大核的形式为生物化学纯化提供了丰富的起始材料[1]。使用这种方法，Allis小组将这种核组蛋白乙酰转移酶追踪到与酵母蛋白Gcn 5同源的55 kDa蛋白质[2]。Gcn 5并不是第一个被发现的组蛋白乙酰转移酶;这一区别属于细胞质组蛋白乙酰转移酶Hat 1，该酶是由Rolf Sternglanz及其同事在一年前克隆的[9，10]。福尔斯。然而，Gcn 5在组蛋白乙酰化和转录之间提供了更强的联系，因为Gcn 5已经被鉴定为酵母酿酒酵母中的“衔接蛋白”，其对于转录因子如Gcn 4的转录激活是必需的[11]。因此，Gcn 5作为核组蛋白乙酰转移酶的鉴定提供了一种修饰染色质内组蛋白的酶与基因表达之间的明确联系，支持了Allfrey最初的假设，即组蛋白乙酰化可以作为控制RNA合成的开关。转录研究的新时代很快出现，发现了使组蛋白脱乙酰化的酶（HDAC 1/Rpd 3）[12]，或添加其他化学部分，如甲基（SUV 39 H1）[13]。在最近的统计中，在哺乳动物细胞中已经鉴定出超过16种不同的组蛋白修饰[14]，提供了一个定义染色质结构和生物学的复杂组合网络。
The concept of chromatin as a regulator of gene expression has been the foundation for nearly all studies of eukaryotic transcription over the past 25 years since the discovery of the first nuclear histone acetyltransferase, Gcn5, by Jim Brownell and David Allis [1, 2]. The histone proteins that form the building blocks of chromatin restrict access to the underlying DNA, and as early as the 1950s and 1960s it was clear that the presence of histones was inhibitory to RNA synthesis. The observation that histones could be chemically modified by the post-translational addition of acetyl or methyl groups [3, 4] led to the idea, first championed by Vincent Allfrey, that histone acetylation could act as a switch to control transcription [5]. Multiple in vitro studies in the following decades supported the idea that acetylation of histones could stimulate transcription from a chromatin template (reviewed in [6, 7]). Moreover, histone acetylation clearly correlated with active transcription within cells [6, 7]. However, the lack of any good candidates for enzymes that could add (or remove) the acetyl mark to histones within the nucleus was a major stumbling block to understanding how histone acetylation could control gene expression.In [8] in this Special Issue, Jim Brownell and David Allis describe the intense search for this nuclear histone acetyltransferase activity, which succeeded due to clever biochemical approaches combined with use of a underappreciated organism, Tetrahymena thermophila, that provided a rich starting material for biochemical purifications in the form of its specialized transcriptionally active macronuclei [1]. Using this approach, the Allis group tracked this nuclear histone acetyltransferase down to a 55 kDa protein that was homologous to a yeast protein, Gcn5 [2]. Gcn5 was not the first histone acetyltransferase to be identified; that distinction falls to the cytoplasmic histone acetyltransferase Hat1 that was cloned just one year earlier by Rolf Sternglanz and colleagues [9, 10]. However, Gcn5 provided a much stronger link between histone acetylation and transcription because Gcn5 had already been identified as an “adaptor protein” in the yeast Saccharomyces cerevisiae that was necessary for transcription activation by transcription factors such as Gcn4 [11]. Thus, the identification of Gcn5 as a nuclear histone acetyltransferase provided a clear connection between an enzyme that modified histones within chromatin and gene expression, supporting Allfrey's original hypothesis that histone acetylation could act as a switch to control RNA synthesis. A new era in transcription research quickly emerged with the discovery of enzymes that deacetylate histones (HDAC1/Rpd3)[12], or add other chemical moieties like methyl groups (SUV39H1)[13]. At the last count, more than 16 different histone modifications have been identified in mammalian cells [14], providing a complex combinatorial network that defines chromatin structure and biology.