Stability and folding pathways of tetra-nucleosome from six-dimensional free energy surface.
Stability and folding pathways of tetra-nucleosome from six-dimensional free energy surface.
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DOI：
10.1038/s41467-021-21377-z
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发表时间：
2021-02-17
影响因子：
16.6
通讯作者：
Zhang B
中科院分区：
文献类型：
--
作者：
Ding X;Lin X;Zhang B
染色质的三维结构有望在调控基因组功能中发挥关键作用。其结构和动力学的高分辨率表征可以提高我们对基因调控机制的理解，但仍然具有挑战性。使用近原子模型，在残基和碱基对分辨率上保留蛋白质- dna相互作用的化学特异性，我们研究了四核小体的稳定性和折叠途径。采用先进的采样技术进行的动态模拟揭示了连接开放染色质配置与之字形晶体结构的多种途径。沿着模拟折叠途径的中间状态类似于原位实验中报道的染色质配置。我们进一步通过深度学习方法确定了一个六维自由能表面作为核小体间距离的函数。锯齿状结构确实可以看作是表面的全局最小值。然而，相对于部分展开的原位构型，它不受大量的青睐。化学扰动如组蛋白H4尾部乙酰化和热波动可以进一步倾斜能量平衡以稳定中间状态。我们的研究提供了对各种报道的染色质结构之间的联系的见解，并对30nm纤维的原位相关性有影响。染色质的三维结构在调控基因组功能中起着至关重要的作用。在这里，作者应用近原子模型来研究染色质折叠单元-四核小体-的结构和动力学，以提供对染色质折叠方式的见解。
The three-dimensional organization of chromatin is expected to play critical roles in regulating genome functions. High-resolution characterization of its structure and dynamics could improve our understanding of gene regulation mechanisms but has remained challenging. Using a near-atomistic model that preserves the chemical specificity of protein-DNA interactions at residue and base-pair resolution, we studied the stability and folding pathways of a tetra-nucleosome. Dynamical simulations performed with an advanced sampling technique uncovered multiple pathways that connect open chromatin configurations with the zigzag crystal structure. Intermediate states along the simulated folding pathways resemble chromatin configurations reported from in situ experiments. We further determined a six-dimensional free energy surface as a function of the inter-nucleosome distances via a deep learning approach. The zigzag structure can indeed be seen as the global minimum of the surface. However, it is not favored by a significant amount relative to the partially unfolded, in situ configurations. Chemical perturbations such as histone H4 tail acetylation and thermal fluctuations can further tilt the energetic balance to stabilize intermediate states. Our study provides insight into the connection between various reported chromatin configurations and has implications on the in situ relevance of the 30 nm fiber. The three-dimensional organization of chromatin plays critical roles in regulating genome function. Here the authors apply a near atomistic model to study the structure and dynamics of the chromatin folding unit - the tetra-nucleosome - to provide insight into how chromatin folds.
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影响因子：
3.4
作者：
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通讯作者：
Schiessel, Helmut
DOI：
10.1073/pnas.1816424116
发表时间：
2019-03-12
影响因子：
11.1
作者：
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影响因子：
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作者：
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影响因子：
3.3
作者：
Bascom, Gavin D.;Kim, Taejin;Schlick, Tamar
通讯作者：
Schlick, Tamar
影响因子：
3.3
作者：
Cai S;Böck D;Pilhofer M;Gan L
通讯作者：
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