Wang Xiao-Tao, Cui Wang, Peng Cheng
Hubei Key Laboratory of Agricultural Bioinformatics, College of Informatics, Huazhong Agricultural University, Wuhan 430070, China.
Nucleic Acids Res. 2017 Nov 2;45(19):e163. doi: 10.1093/nar/gkx735.
A current question in the high-order organization of chromatin is whether topologically associating domains (TADs) are distinct from other hierarchical chromatin domains. However, due to the unclear TAD definition in tradition, the structural and functional uniqueness of TAD is not well studied. In this work, we refined TAD definition by further constraining TADs to the optimal separation on global intra-chromosomal interactions. Inspired by this constraint, we developed a novel method, called HiTAD, to detect hierarchical TADs from Hi-C chromatin interactions. HiTAD performs well in domain sensitivity, replicate reproducibility and inter cell-type conservation. With a novel domain-based alignment proposed by us, we defined several types of hierarchical TAD changes which were not systematically studied previously, and subsequently used them to reveal that TADs and sub-TADs differed statistically in correlating chromosomal compartment, replication timing and gene transcription. Finally, our work also has the implication that the refinement of TAD definition could be achieved by only utilizing chromatin interactions, at least in part. HiTAD is freely available online.
在染色质的高阶组织中，当前一个问题是拓扑相关结构域（TADs）是否与其他层次的染色质结构域不同。然而，由于传统上TAD的定义不明确，TAD的结构和功能独特性尚未得到充分研究。在这项工作中，我们通过进一步将TADs限制在全基因组染色体内相互作用的最佳分离上，对TAD定义进行了细化。受此限制启发，我们开发了一种名为HiTAD的新方法，用于从Hi-C染色质相互作用中检测层次化的TADs。HiTAD在结构域敏感性、重复可重复性和细胞类型间保守性方面表现良好。通过我们提出的一种基于结构域的新比对方法，我们定义了几种以前未系统研究过的层次化TAD变化类型，随后利用它们揭示了TADs和亚TADs在与染色体区室、复制时间和基因转录的相关性上存在统计学差异。最后，我们的工作还表明，至少在一定程度上，仅利用染色质相互作用就可以实现TAD定义的细化。HiTAD可在网上免费获取。
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