Interaction of HP1 and Brg1/Brm with the globular domain of histone H3 is required for HP1-mediated repression.
Interaction of HP1 and Brg1/Brm with the globular domain of histone H3 is required for HP1-mediated repression.
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DOI：
10.1371/journal.pgen.1000769
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发表时间：
2009-12
期刊：
影响因子：
4.5
通讯作者：
Muchardt C
中科院分区：
文献类型：
--
作者：
Lavigne M;Eskeland R;Azebi S;Saint-André V;Jang SM;Batsché E;Fan HY;Kingston RE;Imhof A;Muchardt C
富含异染色质的HP 1蛋白在转录调控中起关键作用。这些蛋白质含有两个相关的结构域，称为染色体结构域和染色阴影结构域。所述色域结合在赖氨酸9上甲基化的组蛋白H3尾部。然而，在体内和体外实验表明，HP 1蛋白质的天然甲基化染色质的亲和力是相对较差的，DNA复制过程中发生的染色质的开放，促进其结合到核小体。这些观察结果促使我们研究HP 1蛋白是否具有额外的组蛋白结合活性，设想对可能被核小体结构封闭的区域的亲和力。我们发现，chromoshadow域相互作用与组蛋白H3在一个区域位于部分内的核小体桶在核小体的入口/出口点。有趣的是，该区域也与人SWI/SNF复合物的催化亚基接触。在体外，有效的SWI/SNF重塑需要这种接触，并在HP 1蛋白存在下受到抑制。SWI/SNF和HP 1蛋白之间的拮抗作用在体内也在一系列干扰素调节的基因上观察到。最后，我们表明，SWI/SNF活性有利于加载的HP 1蛋白质染色质在体内和体外。总之，我们的数据表明，HP 1 chromoshadow域可以受益于核小体结构的开放，结合染色质，HP 1蛋白利用这一特性来检测和逮捕不必要的染色质重塑。HP 1蛋白是转录调节因子，经常与基因沉默相关，基因沉默是一种涉及密集染色质掩蔽启动子DNA的现象。由于它们的染色体结构域，这些蛋白质可以读取并结合表观遗传标记，该标记在许多未表达的基因上存在于核小体表面的组蛋白H3（染色质的基本包装单位）上。然而，与该标记的结合并不能解释HP 1蛋白的抑制活性。在这里，我们表明，这些蛋白质可以建立与组蛋白H3的第二次接触，独立的表观遗传标记。这第二个接触点位于核小体内部，在一个可能无法接近的位置。有趣的是，该位点也与SWI/SNF复合物的亚基接触，并且这种接触是SWI/SNF催化的ATP依赖性染色质重塑所必需的。我们提供的证据表明，HP 1蛋白使用SWI/SNF染色质重塑获得核小体内的接触位点，并通过与SWI/SNF竞争在该位置的结合来防止进一步重塑。这些观察结果使我们认为HP 1蛋白在启动子上起看门人的作用，检测和阻止内部核小体位点的不必要暴露。
The heterochromatin-enriched HP1 proteins play a critical role in regulation of transcription. These proteins contain two related domains known as the chromo- and the chromoshadow-domain. The chromo-domain binds histone H3 tails methylated on lysine 9. However, in vivo and in vitro experiments have shown that the affinity of HP1 proteins to native methylated chromatin is relatively poor and that the opening of chromatin occurring during DNA replication facilitates their binding to nucleosomes. These observations prompted us to investigate whether HP1 proteins have additional histone binding activities, envisioning also affinity for regions potentially occluded by the nucleosome structure. We find that the chromoshadow-domain interacts with histone H3 in a region located partially inside the nucleosomal barrel at the entry/exit point of the nucleosome. Interestingly, this region is also contacted by the catalytic subunits of the human SWI/SNF complex. In vitro, efficient SWI/SNF remodeling requires this contact and is inhibited in the presence of HP1 proteins. The antagonism between SWI/SNF and HP1 proteins is also observed in vivo on a series of interferon-regulated genes. Finally, we show that SWI/SNF activity favors loading of HP1 proteins to chromatin both in vivo and in vitro. Altogether, our data suggest that HP1 chromoshadow-domains can benefit from the opening of nucleosomal structures to bind chromatin and that HP1 proteins use this property to detect and arrest unwanted chromatin remodeling. HP1 proteins are transcriptional regulators frequently associated with gene silencing, a phenomenon involving masking of promoter DNA by dense chromatin. Owing to their chromo-domain, these proteins can read and bind an epigenetic mark that on many non-expressed genes is present on histone H3 at the surface of the nucleosome (the fundamental packing unit of chromatin). However, the binding to this mark does not explain the repressing activity of HP1 proteins. Here, we show that these proteins can establish a second contact with histone H3, independently of the epigenetic mark. This second contact site is located inside the nucleosome, in a position likely to be inaccessible. Interestingly, this site is also contacted by a subunit of the SWI/SNF complex and this contact is required for the ATP-dependent chromatin remodeling catalyzed by SWI/SNF. We provide evidence suggesting that HP1 proteins use the SWI/SNF chromatin remodeling to gain access to the contact site inside the nucleosome and to prevent further remodeling by competing with SWI/SNF for binding at this position. These observations lead us to suggest that HP1 proteins function as gatekeepers on promoters, detecting and stopping unwanted exposure of internal nucleosomal sites.
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影响因子：
64.5
作者：
Czermin, B;Melfi, R;Pirrotta, V
通讯作者：
Pirrotta, V
影响因子：
21.3
作者：
Huang, M;Qian, F;Wen, ZL
通讯作者：
Wen, ZL
DOI：
10.1073/pnas.95.13.7322
发表时间：
1998-06-23
影响因子：
11.1
作者：
Lehming, N;Le Saux, A;Ptashne, M
通讯作者：
Ptashne, M
影响因子：
16
作者：
Lavigne, M;Francis, NJ;Kingston, RE
通讯作者：
Kingston, RE
DOI：
10.1083/jcb.200804041
发表时间：
2008-11-17
期刊：
The Journal of cell biology
影响因子：
--
作者：
Aucott R;Bullwinkel J;Yu Y;Shi W;Billur M;Brown JP;Menzel U;Kioussis D;Wang G;Reisert I;Weimer J;Pandita RK;Sharma GG;Pandita TK;Fundele R;Singh PB
通讯作者：
Singh PB