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基因组三维结构在基因表达调控中发挥重要作用,染色质拓扑关联结构域(topologically associated domain,TAD)是DNA复制和基因转录的基本功能单位,也是DNA损伤修复的功能单元,在辐射诱导的DNA损伤修复中发挥重要作用。近期研究表明,TAD并非是完全独立的结构单元,其内部常呈现多层级结构,对基因表达具有重要调控作用。为探究TAD多层级结构在细胞辐射响应中的作用,本研究使用TAD层级结构识别算法OnTAD对Gene expression omnibus数据库中5Gy X射线照射的淋巴细胞、成纤维细胞和毛细血管扩张性共济失调突变(ataxia telangiectasia mutated,ATM)基因缺陷的成纤维细胞,共26个样本的Hi-C(high-through chromosome conformation capture,Hi-C)数据进行分析,发现辐射后细胞的TAD层级结构出现规律性变化,高层级TAD缺失较多,低层级TAD相对保守;辐射诱导的TAD层级结构变化通过调节基因表达参与细胞辐射响应;ATM是辐射诱导TAD层级结构变化和恢复的重要因子。本研究为从TAD多层级结构角度理解基因组三维结构在细胞辐射响应中的作用提供了新思路。 相似文献
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Xheni Karaboja Zhongqing Ren Hugo B. Brandão Payel Paul David Z. Rudner Xindan Wang 《Molecular cell》2021,81(4):756-766.e8
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AbstractPhosphorylation of protein is critical for various cell processes, which preferentially happens in intrinsically disordered proteins (IDPs). How phosphorylation modulates structural ensemble of disordered peptide remains largely unexplored. Here, using replica exchange molecular dynamics (REMD) and Markov state model (MSM), the conformational distribution and kinetics of p53 N-terminal transactivation domain (TAD) 2 as well as its dual-site phosphorylated form (pSer46, pThr55) were simulated. It reveals that the dual phosphorylation does not change overall size and secondary structure element fraction, while a change in the distribution of hydrogen bonds induces slightly more pre-existing bound helical conformations. MSM analysis indicates that the dual phosphorylation accelerates conformation exchange between disordered and order-like states in target-binding region. It suggests that p53 TAD2 after phosphorylation would be more apt to bind to both the human p62 pleckstrin homology (PH) domain and the yeast tfb1?PH domain through different binding mechanism, where experimentally it exhibits an extended and α-helix conformation, respectively, with increased binding strength in both complexes. Our study implies except binding interface, both conformation ensemble and kinetics should be considered for the effects of phosphorylation on IDPs. Abbreviations IDPs intrinsically disordered proteins REMD replica exchange molecular dynamics MSM Markov state model TAD transactivation domain PH pleckstrin homology PRR proline-rich region DBD DNA-binding domain TET Tetramerization domain REG regulatory domain MD molecular dynamics PME particle-mesh Ewald TICA time-lagged independent component analysis CK Chapman–Kolmogorov GMRQ generalized matrix Rayleigh quotient SARW self-avoiding random walk KID kinase-inducible domain MFPT mean first passage time DSSP definition of secondary structure of proteins RMSD root mean square deviation Rg radius of gyration Ree end to end distance Communicated by Ramaswamy H. Sarma 相似文献
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