Sequence requirements for combinatorial recognition of histone H3 by the MRG15 and Pf1 subunits of the Rpd3S/Sin3S corepressor complex.
Sequence requirements for combinatorial recognition of histone H3 by the MRG15 and Pf1 subunits of the Rpd3S/Sin3S corepressor complex.
复制标题
DOI：
10.1016/j.jmb.2012.06.013
复制
发表时间：
2012-09-28
影响因子：
5.6
通讯作者：
Radhakrishnan, Ishwar
中科院分区：
文献类型：
--
作者：
Kumar, Ganesan Senthil;Chang, William;Xie, Tao;Patel, Anand;Zhang, Yongbo;Wang, Gang Greg;David, Gregory;Radhakrishnan, Ishwar
真核生物中基因组基因座的转录输出部分由关键效应蛋白读取和解释的组蛋白修饰模式决定。组蛋白去乙酰化酶活性的进化保守的Rpd 3S/Sin 3S复合物是至关重要的抑制异常转录的基因内区域内的隐蔽起始位点。复合物的精确靶向依赖于MRG 15和Pf 1亚基的染色质结合活性。尽管MRG 15染色体结构域（CD）的分子靶点被认为是H3 K36 me 2/3，但Pf 1植物同源结构域1（PHD 1）的精确分子靶点仍然难以捉摸。我们发现Pf 1 PHD 1优先结合组蛋白H3的未修饰的末端N端（H3 K4 me 0），而不结合H3 K4 me 2/3，后者富集在基因的启动子和5′区。与先前表征的CD和PHD结构域以微摩尔亲和力结合其靶点不同，MRG 15 CD和Pf 1 PHD 1均以>100 μM的亲和力结合其靶点，这解释了为什么Rpd 3S/Sin 3S复合物靶向染色质需要MRG 15 CD和Pf 1 PHD 1结构域。我们的研究结果还表明，二价，而不是协同性，是Pf 1和MRG 15结合联合收割机从事H3在生物学上有意义的方式的运作机制。最后，这些研究揭示了Pf 1 PHD 1在接合MRG 15 MRG结构域中的意外作用，尽管是以Pf 1 MRG结合结构域（MBD）依赖性方式，这意味着MRG 15 MRG-Pf 1 MBD相互作用在Rpd 3S/Sin 3S复合物的染色质靶向中起关键作用。
The transcriptional output at a genomic locus in eukaryotes is determined, in part, by the pattern of histone modifications that are read and interpreted by key effector proteins. The histone deacetylase activity of the evolutionarily-conserved Rpd3S/Sin3S complex is crucial for suppressing aberrant transcription from cryptic start sites within intragenic regions of actively transcribed genes. Precise targeting of the complex relies on the chromatin binding activities of the MRG15 and Pf1 subunits. Whereas the molecular target of the MRG15 chromodomain (CD) has been suggested to be H3K36me2/3, the precise molecular target of the Pf1 plant homeodomain 1 (PHD1) has remained elusive. Here we show that Pf1 PHD1 binds preferentially to the unmodified extreme N-terminus of histone H3 (H3K4me0) but not to H3K4me2/3, which are enriched in the promoter and 5′ regions of genes. Unlike previously characterized CD and PHD domains that bind to their targets with micromolar affinity, both MRG15 CD and Pf1 PHD1 bind to their targets with >100 μM affinity, offering an explanation for why both MRG15 CD and Pf1 PHD1 domains are required to target the Rpd3S/Sin3S complex to chromatin. Our results also suggest that bivalency, rather than cooperativity, is the operative mechanism by which Pf1 and MRG15 combine to engage H3 in a biologically significant manner. Finally, the studies reveal an unanticipated role of Pf1 PHD1 in engaging the MRG15 MRG domain, albeit in a Pf1 MRG-binding domain (MBD)-dependent manner, implying a key role for the MRG15 MRG-Pf1 MBD interaction in chromatin targeting of the Rpd3S/Sin3S complex.
登录
查看更多内容
影响因子：
64.5
作者：
Malovannaya A;Lanz RB;Jung SY;Bulynko Y;Le NT;Chan DW;Ding C;Shi Y;Yucer N;Krenciute G;Kim BJ;Li C;Chen R;Li W;Wang Y;O'Malley BW;Qin J
通讯作者：
Qin J
DOI：
10.1016/j.bbagrm.2009.05.007
发表时间：
2009-06
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Grzenda A;Lomberk G;Zhang JS;Urrutia R
通讯作者：
Urrutia R
影响因子：
--
作者：
Hayakawa T;Nakayama J
通讯作者：
Nakayama J
影响因子：
16
作者：
Joshi, AA;Struhl, K
通讯作者：
Struhl, K
影响因子：
14.9
作者：
Chignola, Francesca;Gaetani, Massimiliano;Musco, Giovanna
通讯作者：
Musco, Giovanna