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发表于 2010-4-12 23:12 |只看该作者 |倒序浏览 |打印

本帖最后由 yusheen 于 2010-4-12 23:24 编辑 & d$ r- Y6 z. j" Z/ P! ]
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在4月2日的《科学》杂志上，刊发了国家生命科学研究院(北京生命科学研究所)朱冰研究员为通讯作者的研究论文：Partitioning of Histone H3-H4 Tetramers During DNA Replication–Dependent Chromatin Assembly. 就DNA复制过程中核小体中H3-H4四聚体是否发生了拆分进行了详细研究。法国Laboratory of Nuclear Dynamics and Genome Plasticity的研究人员在同一期的杂志上配发了评论文章。现将该评论文章发于此，并尝试进行了翻译，供参考。正在中国科学院上海生命科学研究院访问的James Watson看到中国科学家的这一成就时应该会考虑Molecular Biology of the gene再版时修改关于H3-H4四聚体的观点吧。
MOLECULAR BIOLOGY:
Mixing or Not Mixing
Dominique Ray-Gallet and Geneviève Almouzni 2 [: H- P3 J% w
Laboratory of Nuclear Dynamics and Genome Plasticity, UMR218 CNRS/Institut Curie, 26 rue d'Ulm, 75248 Paris Cedex 05, France.
E-mail: Genevieve.Almouzni@curie.fr% H: T7 J; s" J# {6 o# f* p/ i
Beyond DNA information, the organization of the proteins and DNA that constitute chromatin represents a means to regulate genome function (1). The inheritance and maintenance of the DNA sequence has been explained by a semiconservative mechanism of replication in which a complementary new strand of DNA is synthesized along each parental strand, resulting in an inherited double-stranded molecule that contains old and new DNA. But how is the inheritance of epigenetic traits—modifications of chromatin proteins (histones) and DNA that do not alter the sequence—affected by dynamic changes in chromatin organization during eukaryotic cell division? On page 94 of this issue, Xu et al. (2) explore how parental (old) and newly synthesized histones associate after replication., W7 f) D% u& d+ j; m8 W0 t
除DNA包含的信息外，蛋白质和DNA构成染色质的组织形式代表了一种调节基因组功能的途径（1）。DNA序列的遗传和维持可以被复制的半保留机制所解释，在这一机制中互补新链DNA沿着每条父本链合成，产生了可遗传的含有新旧DNA的双链分子。但是在真核细胞分裂中，遗传的表观遗传特性---染色质蛋白（组蛋白）和DNA的修饰（序列没有改变）是如何受到染色质的组装的动态变化影响的呢？在本期的94页，徐（墨）等人探讨了新合成的组蛋白和原有的组蛋白（来自亲本）是如何发生联系的（2）。
The basic unit of chromatin, the nucleosome, has a core particle of eight histones—two pairs of histone H3-H4 as a tetramer flanked by two dimers of histone H2A-H2B. Histones can be present in distinct forms or variants, and they may harbor specific post-translational modifications that can define a given epigenome (1, 3). How do these particular markings sustain passage through replication? An attractive hypothesis has been a semiconservative mechanism in which parental histones are combined with newly synthesized histones within the same core nucleosome. The presence of parental information as a template to reproduce the same marks on new histones provides a convenient means to ensure accurate reproduction of the initial marking at the same place. But can parental and new histones mix? & L. Y# G' j: D
染色质的基本单位--核小体，有一个由8个组蛋白组成的核心颗粒--- 各2对 H3、H4组蛋白组成的四聚体，其两侧是两个由H2A、H2B组成的二聚体。组蛋白可以以不同形式的变体存在，这些组蛋白含有特异的翻译后修饰，形成复杂的表观基因组学（epigenome）密码（1，3）。那么这些特异性的标记在复制过程中是如何维持的呢？一个有吸引力的假说是半保留的机制，在这一机制中，亲本的组蛋白和新合成的组蛋白共存于同一核小体核心中。父本信息的存在提供了在新合成的组蛋白上产生相同标记的模板【译者注：实际上是招募了识别原有标记的酶来对新合成的组蛋白进行修饰】，这一便利的途径确保了在同一地方对起初的标记进行准确的复制。但是，新旧组蛋白可以混合吗？
Histones H2A-H2B readily exchange as dimers, but H3-H4 tetramers are thought not to split (4). However, newly synthesized H3 and H4 can exist as dimers when associated with histone chaperones (5–8), spurring the debate. 0 L6 g6 [/ F# B# S
Xu et al. use isotope labeling and mass spectrometry analysis of histone content to explore how new and old H3-H4 dimers associate after replication. Their model system is based on conditional expression in cultured human cells of tagged versions of distinct variants of histone H3: H3.1 and H3.3. H3.1 is a replicative histone variant, with a peak of expression in S phase of the cell division cycle, and is mostly incorporated into duplicated chromatin in a manner that is coupled to DNA replication (3). H3.3, known as a replacement variant, is expressed throughout all phases of the cell cycle and in quiescence, and can be incorporated into chromatin independently of DNA synthesis (3).
H2A-H2B很容易以二聚体形式进行交换【实际上是和新合成的H2A-H2B二聚体混合在一起】，但原有的H3- H4组成的四聚体一般认为是不被拆分的（4）。然而，新合成的H3、 H4组蛋白在和组蛋白分子伴侣互作时可以以二聚体形式存在（5-8），这就使得H3-H4组成的四聚体是否可以拆分的辩论显得异常激烈。徐（墨）等人利用稳定同位素标记和的质谱分析技术来分析组蛋白含量，以此探讨新旧的H3 - H4二聚体在DNA复制后是如何相互联系的。他们的研究模型系统是基于标记的H3组蛋白不同的变体（H3.1和H3.3）在培养的人类细胞中有条件的表达： H3.1是一个复制型的组蛋白变体，其在细胞分裂周期的S期有最高峰的表达，以一种和DNA复制相偶联的方式经常参入到复制的染色质中（3）。众所周知H3.3是一个可替代的变体，其在细胞周期的任一阶段以及细胞的静止时期都可以表达，可以不依赖于DNA的合成而独立参入到染色质中（3）。5 ^7 F2 j+ a+ w, c% J
Xu et al. did a genome-wide analysis of H3.1 incorporation into nucleosomes and observed no splitting of the H3.1-H4 tetramer, confirming earlier work on H3. Yet the H3.3-H4 tetramer did split. Both H3.1 and H3.3 variants were found in new and old nucleosomes and in mixed nucleosomes for H3.3. The authors considered the possibility that when selecting cells with H3.1 or H3.3 for analysis, they may have examined different populations of nucleosomes arising from distinct genomic regions. This is particularly critical for H3.3, which has been associated with actively transcribed regions. The question is whether splitting is region-specific or variant-specific. A previous analysis showed that in the vicinity of H3.3, H3.1 presented modifications similar to those found on H3.3 (9). In this case, what would the fate be of H3.1 nucleosomes that flank H3.3—would they split or not? It may be that H3.1 has a similar splitting feature when it is in the vicinity of H3.3. 1 B# W+ S/ {5 `1 ~. o9 V! e% i! ?
徐（墨）等人在全基因组范围内分析了H3.1参入到核小体的情况，观察到没有H3.1 - H4的四聚体分裂或拆分，这证实了早期有关H3组蛋白的研究工作。然而，（有趣的是，）H3.3 - H4四聚体却发生了分裂或拆分。在新旧核小体以及混合的核心体中都发现了H3.1和H3.3的变体。作者认为，造成这种可能性的原因是：当选择有H3.1或H3.3变体的细胞进行分析时，他们也许检测到了从基因组不同区域来源的不同类群核小体。这对H3.3变体来说至关重要，这是因为它和基因组的活性转录区域有关。由此引出的问题是，四聚体的拆分是区域特异性的呢还是变体特异性的呢？一个以前的分析表明，在H3.3附近，H3.1表现出的修饰类似于以前发现的H3.3修饰（9）。在这种情况下，位于H3.3侧翼的H3.1核小体的命运会是怎样的呢---他们会发生拆分吗？也许H3.1在H3.3附近时有类似的分裂的特性。8 @( C" D1 i, F G) m
Clearly, histone splitting is part of the histone inheritance picture during chromatin duplication, and three alternative modes for H3-H4 partitioning (10) can be considered as real (see the figure). The next challenge is to explore how these modes of distribution become articulated with the transmission of histone marks. The nonmixing options are compatible with proposed models in which histone marks are copied from neighboring histones, as observed with tightly packed heterochromatin regions (1, 10–12). Yet, the possibility of an intranucleosome histone template for modifications may apply to particular genomic regions to ensure memory of critical active marks (12, 13). Future work will investigate how the choice between histone splitting and nonsplitting is made within a cell and whether this is regulated during cellular life or during development.
显然，组蛋白分裂是在染色质复制过程中组蛋白遗传图景中重要的一部分，H3- H4四聚体的拆分（10）可以总结为三种替代的模式（见评论文章的图）。下一个挑战是要探讨这些模式的分布是如何和组蛋白标记传递密切相关的。在这些模式中，组蛋白不混合（nonmixing）的抉择与以前提出的组蛋白的标记是从邻近组蛋白所拷贝过来的模型相兼容，正如紧密包装的异染色质区域所观察到的现象那样（1，10-12）。然而，核小体内的组蛋白为修饰提供了模板的可能性也许适用于基因组的特定区域，以确保关键活性标记的记忆保持（12，13）。将来的的工作将研究细胞中组蛋白的拆分和不拆分的选择是如何决定的，以及这种决定在细胞生命和发育中是如何受到调节。
References # ]0 t* m3 F% K* o
1. C. D. Allis, T. Jenuwein, D. Reinberg, Epigenetics (Cold Spring Harbor Laboratory Press, New York, 2006).
2. M. Xu et al., Science 328, 94 (2010).
3. K. Sarma, D. Reinberg, Nat. Rev. Mol. Cell Biol. 6, 139 (2005). ; H1 V% t9 K0 l$ u8 k0 o3 x7 d
4. A. T. Annunziato, J. Biol. Chem. 280, 12065 (2005).[Free Full Text]
5. H. Tagami, D. Ray-Gallet, G. Almouzni, Y. Nakatani, Cell 116, 51 (2004). - \. g8 i1 W$ R/ ?$ P6 l2 J5 [
6. C. M. English, N. K. Maluf, B. Tripet, M. E. Churchill, J. S. Tyler, Biochemistry 44, 13673 (2005).
7. L. J. Benson et al., J. Biol. Chem. 281, 9287 (2006).+ U' O; F% O* y8 D1 U; o: c
8. R. Natsume et al., Nature 446, 338 (2007).
9. A. Loyola, G. Almouzni et al., Mol. Cell 24, 309 (2006).
10. Y. Nakatani, D. Ray-Gallet, J. P. Quivy, H. Tagami, G. Almouzni, Cold Spring Harb. Symp. Quant. Biol. 69, 273 (2004).
11. J. Nakayama et al., Science 292, 110 (2001).
12. A. V. Probst, E. Dunleavy, G. Almouzni, Nat. Rev. Mol. Cell Biol. 10, 192 (2009).
13. S. Henikoff, J. G. Henikoff, A. Sakai, G. B. Loeb, K. Ahmad, Genome Res. 19, 460 (2008). 5 C+ x/ r9 Z5 } x; w

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