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重新破解核小体定位密码。

Re-cracking the nucleosome positioning code.

作者信息

Segal Mark R

机构信息

University of California, San Francisco, USA.

出版信息

Stat Appl Genet Mol Biol. 2008;7(1):Article14. doi: 10.2202/1544-6115.1367. Epub 2008 Apr 21.

Abstract

Nucleosomes, the fundamental repeating subunits of all eukaryotic chromatin, are responsible for packaging DNA into chromosomes inside the cell nucleus and controlling gene expression. While it has been well established that nucleosomes exhibit higher affinity for select DNA sequences, until recently it was unclear whether such preferences exerted a significant, genome-wide effect on nucleosome positioning in vivo. This question was seemingly and recently resolved in the affirmative: a wide-ranging series of experimental and computational analyses provided extensive evidence that the instructions for wrapping DNA around nucleosomes are contained in the DNA itself. This subsequently labeled second genetic code was based on data-driven, structural, and biophysical considerations. It was subjected to an extensive suite of validation procedures, with one conclusion being that intrinsic, genome-encoded, nucleosome organization explains approximately 50% of in vivo nucleosome positioning. Here, we revisit both the nature of the underlying sequence preferences, and the performance of the proposed code. A series of new analyses, employing spectral envelope (Fourier transform) methods for assessing key sequence periodicities, classification techniques for evaluating predictive performance, and discriminatory motif finding methods for devising alternate models, are applied. The findings from the respective analyses indicate that signature dinucleotide periodicities are absent from the bulk of the high affinity nucleosome-bound sequences, and that the predictive performance of the code is modest. We conclude that further exploration of the role of sequence-based preferences in genome-wide nucleosome positioning is warranted. This work offers a methodologic counterpart to a recent, high resolution determination of nucleosome positioning that also questions the accuracy of the proposed code and, further, provides illustrations of techniques useful in assessing sequence periodicity and predictive performance.

摘要

核小体是所有真核染色质的基本重复亚基,负责将DNA包装成细胞核内的染色体并控制基因表达。虽然已经充分证实核小体对特定DNA序列具有更高的亲和力,但直到最近,尚不清楚这种偏好是否在体内对核小体定位产生显著的全基因组效应。这个问题最近似乎得到了肯定的解决:一系列广泛的实验和计算分析提供了大量证据,表明将DNA缠绕在核小体上的指令包含在DNA本身中。这种随后被标记的第二遗传密码是基于数据驱动、结构和生物物理方面的考虑。它经过了一系列广泛的验证程序,其中一个结论是,内在的、基因组编码的核小体组织解释了体内约50%的核小体定位。在这里,我们重新审视潜在序列偏好的本质以及所提出密码的性能。我们应用了一系列新的分析方法,包括用于评估关键序列周期性的频谱包络(傅里叶变换)方法、用于评估预测性能的分类技术以及用于设计替代模型的鉴别基序查找方法。各自分析的结果表明,在大多数高亲和力核小体结合序列中不存在特征性二核苷酸周期性,并且该密码的预测性能一般。我们得出结论,有必要进一步探索基于序列的偏好在全基因组核小体定位中的作用。这项工作为最近高分辨率确定核小体定位提供了一种方法学对应物,该确定也对所提出密码的准确性提出了质疑,并且进一步提供了有助于评估序列周期性和预测性能的技术示例。

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