Using DNA mechanics to predict in vitro nucleosome positions and formation energies.
Using DNA mechanics to predict in vitro nucleosome positions and formation energies.
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DOI：
10.1093/nar/gkp475
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发表时间：
2009-08
影响因子：
14.9
通讯作者：
Siggia ED
中科院分区：
文献类型：
--
作者：
Morozov AV;Fortney K;Gaykalova DA;Studitsky VM;Widom J;Siggia ED
在真核基因组中，核小体的功能是压缩DNA，并通过简单的物理封闭和为许多共价表遗传学标签提供底物来调节对DNA的访问。虽然与其他DNA结合因子的竞争和染色质重塑酶的作用显著影响体内核小体的形成，但核小体在体外的位置仅由空间排斥和序列决定。我们已经开发了一个生物物理模型DNABEND，用于DNA弯曲能的序列相关性，并根据一组体外核小体形成的自由能和一组高分辨率绘制的体外核小体位置来验证它。我们还首次对核小体DNA几何结构进行了从头算预测，并对照核小体晶体结构检查了其准确性。我们使用DNABEND设计了强组蛋白结合序列和弱组蛋白结合序列，并测量了相应的核小体形成自由能。我们发现，DNABEND可以成功地预测体外核小体的位置和自由能，为组蛋白-DNA相互作用的内在序列依赖性提供了物理解释。
In eukaryotic genomes, nucleosomes function to compact DNA and to regulate access to it both by simple physical occlusion and by providing the substrate for numerous covalent epigenetic tags. While competition with other DNA-binding factors and action of chromatin remodeling enzymes significantly affect nucleosome formation in vivo, nucleosome positions in vitro are determined by steric exclusion and sequence alone. We have developed a biophysical model, DNABEND, for the sequence dependence of DNA bending energies, and validated it against a collection of in vitro free energies of nucleosome formation and a set of in vitro nucleosome positions mapped at high resolution. We have also made a first ab initio prediction of nucleosomal DNA geometries, and checked its accuracy against the nucleosome crystal structure. We have used DNABEND to design both strong and weak histone- binding sequences, and measured the corresponding free energies of nucleosome formation. We find that DNABEND can successfully predict in vitro nucleosome positions and free energies, providing a physical explanation for the intrinsic sequence dependence of histone–DNA interactions.
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