Chromatin accessibility reveals insights into androgen receptor activation and transcriptional specificity.
Chromatin accessibility reveals insights into androgen receptor activation and transcriptional specificity.
复制标题
DOI：
10.1186/gb-2012-13-10-r88
复制
发表时间：
2012-10-03
期刊：
影响因子：
12.3
通讯作者：
Febbo PG
中科院分区：
文献类型：
--
作者：
Tewari AK;Yardimci GG;Shibata Y;Sheffield NC;Song L;Taylor BS;Georgiev SG;Coetzee GA;Ohler U;Furey TS;Crawford GE;Febbo PG
表观遗传机制，如染色质的可及性，影响转录因子与DNA的结合和转录特异性。雄激素受体(AR)是男性表型和前列腺癌发病机制的主要调节因子，主要通过配体激活的靶基因转录发挥作用。尽管AR转录特异性的几个决定因素已经被阐明，但我们对染色质可及性和AR功能之间的相互作用的了解仍然不完整。我们使用深度测序通过DNase I超敏反应和mRNA丰度来评估染色质结构，并将这些数据集与三个独立的AR芯片序列数据集配对。我们的分析揭示了染色质可及性的定性和定量差异，这与AR结合和潜在协作因子的基序丰富相对应，其中之一被鉴定为SP1。这些数量上的差异与整个基因组中AR调节的mRNA转录显著相关。DNase I裂解图谱的碱基对分辨显示了与AR-DNA相互作用相关的三种不同的足迹模式，表明AR与基因组相互作用的多种模式。与其他DNA结合因子不同，AR与基因组的结合不仅针对在激素诱导之前可被DNase I切割的区域。AR结合总是与染色质可及性增加相关，从而导致基因表达的变化。此外，我们提出了第一个体内证据，表明很大一部分AR只与完整AR DNA基序的一半结合。这些发现表明染色质结构和AR-DNA结合之间的动态定量关系影响AR转录特异性。
Epigenetic mechanisms such as chromatin accessibility impact transcription factor binding to DNA and transcriptional specificity. The androgen receptor (AR), a master regulator of the male phenotype and prostate cancer pathogenesis, acts primarily through ligand-activated transcription of target genes. Although several determinants of AR transcriptional specificity have been elucidated, our understanding of the interplay between chromatin accessibility and AR function remains incomplete. We used deep sequencing to assess chromatin structure via DNase I hypersensitivity and mRNA abundance, and paired these datasets with three independent AR ChIP-seq datasets. Our analysis revealed qualitative and quantitative differences in chromatin accessibility that corresponded to both AR binding and an enrichment of motifs for potential collaborating factors, one of which was identified as SP1. These quantitative differences were significantly associated with AR-regulated mRNA transcription across the genome. Base-pair resolution of the DNase I cleavage profile revealed three distinct footprinting patterns associated with the AR-DNA interaction, suggesting multiple modes of AR interaction with the genome. In contrast with other DNA-binding factors, AR binding to the genome does not only target regions that are accessible to DNase I cleavage prior to hormone induction. AR binding is invariably associated with an increase in chromatin accessibility and, consequently, changes in gene expression. Furthermore, we present the first in vivo evidence that a significant fraction of AR binds only to half of the full AR DNA motif. These findings indicate a dynamic quantitative relationship between chromatin structure and AR-DNA binding that impacts AR transcriptional specificity.
登录
查看更多内容
影响因子：
30.8
作者：
Carver, Brett S.;Tran, Jennifer;Gopalan, Anuradha;Chen, Zhenbang;Shaikh, Safa;Carracedo, Arkaitz;Alimonti, Andrea;Nardella, Caterina;Varmeh, Shohreh;Scardino, Peter T.;Cordon-Cardo, Carlos;Gerald, William;Pandolfi, Pier Paolo
通讯作者：
Pandolfi, Pier Paolo
影响因子：
82.9
作者：
Chen, CD;Welsbie, DS;Sawyers, CL
通讯作者：
Sawyers, CL
影响因子：
30.8
作者：
He, Housheng Hansen;Meyer, Clifford A.;Shin, Hyunjin;Bailey, Shannon T.;Wei, Gang;Wang, Qianben;Zhang, Yong;Xu, Kexin;Ni, Min;Lupien, Mathieu;Mieczkowski, Piotr;Lieb, Jason D.;Zhao, Keji;Brown, Myles;Liu, X. Shirley
通讯作者：
Liu, X. Shirley
DOI：
10.1126/science.1189992
发表时间：
2010-07-30
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Goldstein AS;Huang J;Guo C;Garraway IP;Witte ON
通讯作者：
Witte ON
影响因子：
82.9
作者：
Craft, N;Shostak, Y;Sawyers, CL
通讯作者：
Sawyers, CL