Targeted H3R26 deimination specifically facilitates estrogen receptor binding by modifying nucleosome structure.
Targeted H3R26 deimination specifically facilitates estrogen receptor binding by modifying nucleosome structure.
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靶向 H3R26 脱亚胺化通过改变核小体结构特异性促进雌激素受体结合
DOI：
10.1371/journal.pgen.1004613
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发表时间：
2014-09
期刊：
影响因子：
4.5
通讯作者：
Coonrod SA
中科院分区：
文献类型：
--
作者：
Guertin MJ;Zhang X;Anguish L;Kim S;Varticovski L;Lis JT;Hager GL;Coonrod SA
转录因子在体内与DNA结合导致染色质修饰剂的募集，所述染色质修饰剂可引起染色质结构的改变，包括组蛋白尾部的修饰。我们以前发现，雌激素受体（ER）靶基因的激活是由肽基精氨酸脱亚胺酶2（PAD 2）催化的组蛋白H3 R26脱亚胺（H3 R26 Cit）。在这里，我们报告，乳腺癌细胞中的ER和H3 R26 Cit的基因组分布是惊人的一致，线性相关，并观察到早在雌二醇治疗后2分钟。H3 R26 Cit谱与先前描述的组蛋白修饰不同，其特征在于尖锐、窄的峰。配对末端MNase ChIP-seq表明，电荷中性的H3 R26 Cit修饰通过改变核小体的精细结构促进ER与DNA的结合。临床上，我们发现PAD 2和H3 R26 Cit水平与乳腺肿瘤中的ER表达相关，并且PAD 2高表达与ER+乳腺癌患者的生存率增加相关。这些发现提供了对转录因子如何进入核小体DNA的深入了解，并暗示PAD 2是ER+乳腺癌的新治疗靶点。
Transcription factor binding to DNA in vivo causes the recruitment of chromatin modifiers that can cause changes in chromatin structure, including the modification of histone tails. We previously showed that estrogen receptor (ER) target gene activation is facilitated by peptidylarginine deiminase 2 (PAD2)-catalyzed histone H3R26 deimination (H3R26Cit). Here we report that the genomic distributions of ER and H3R26Cit in breast cancer cells are strikingly coincident, linearly correlated, and observed as early as 2 minutes following estradiol treatment. The H3R26Cit profile is unlike that of previously described histone modifications and is characterized by sharp, narrow peaks. Paired-end MNase ChIP-seq indicates that the charge-neutral H3R26Cit modification facilitates ER binding to DNA by altering the fine structure of the nucleosome. Clinically, we find that PAD2 and H3R26Cit levels correlate with ER expression in breast tumors and that high PAD2 expression is associated with increased survival in ER+ breast cancer patients. These findings provide insight into how transcription factors gain access to nucleosomal DNA and implicate PAD2 as a novel therapeutic target for ER+ breast cancer.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
11.2
作者：
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影响因子：
16
作者：
Ballare, Cecilia;Castellano, Giancarlo;Beato, Miguel
通讯作者：
Beato, Miguel
影响因子：
7
作者：
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通讯作者：
Liu XS
影响因子：
30.8
作者：
John S;Sabo PJ;Thurman RE;Sung MH;Biddie SC;Johnson TA;Hager GL;Stamatoyannopoulos JA
通讯作者：
Stamatoyannopoulos JA