Contreras Carlos, Villasana Minaya, Hendzel Michael J, Carrero Gustavo
Department of Mathematical and Statistical Sciences, University of Alberta, Edmonton, Alberta, Canada.
Departamento de Cómputo Científico y Estadística, Universidad Simón Bolívar, Caracas, Miranda, Venezuela.
PLoS One. 2018 Jan 19;13(1):e0191562. doi: 10.1371/journal.pone.0191562. eCollection 2018.
Histones H1 or linker histones are highly dynamic proteins that diffuse throughout the cell nucleus and associate with chromatin (DNA and associated proteins). This binding interaction of histone H1 with the chromatin is thought to regulate chromatin organization and DNA accessibility to transcription factors and has been proven to involve a kinetic process characterized by a population that associates weakly with chromatin and rapidly dissociates and another population that resides at a binding site for up to several minutes before dissociating. When considering differences between these two classes of interactions in a mathematical model for the purpose of describing and quantifying the dynamics of histone H1, it becomes apparent that there could be several assembly pathways that explain the kinetic data obtained in living cells. In this work, we model these different pathways using systems of reaction-diffusion equations and carry out a model comparison analysis using FRAP (fluorescence recovery after photobleaching) experimental data from different histone H1 variants to determine the most feasible mechanism to explain histone H1 binding to chromatin. The analysis favors four different chromatin assembly pathways for histone H1 which share common features and provide meaningful biological information on histone H1 dynamics. We show, using perturbation analysis, that the explicit consideration of high- and low-affinity associations of histone H1 with chromatin in the favored assembly pathways improves the interpretation of histone H1 experimental FRAP data. To illustrate the results, we use one of the favored models to assess the kinetic changes of histone H1 after core histone hyperacetylation, and conclude that this post-transcriptional modification does not affect significantly the transition of histone H1 from a weakly bound state to a tightly bound state.
组蛋白H1或连接组蛋白是高度动态的蛋白质，它们在细胞核中扩散并与染色质（DNA及相关蛋白质）结合。组蛋白H1与染色质的这种结合相互作用被认为可调节染色质组织以及转录因子对DNA的可及性，并且已被证明涉及一个动力学过程，其特征是一部分与染色质弱结合并迅速解离，另一部分则在结合位点停留长达几分钟后才解离。在为描述和量化组蛋白H1的动力学而构建的数学模型中考虑这两类相互作用之间的差异时，很明显可能存在几种组装途径可以解释在活细胞中获得的动力学数据。在这项工作中，我们使用反应扩散方程组对这些不同途径进行建模，并使用来自不同组蛋白H1变体的光漂白后荧光恢复（FRAP）实验数据进行模型比较分析，以确定解释组蛋白H1与染色质结合的最可行机制。分析支持组蛋白H1的四种不同染色质组装途径，它们具有共同特征，并提供了有关组蛋白H1动力学的有意义的生物学信息。我们通过微扰分析表明，在有利的组装途径中明确考虑组蛋白H1与染色质的高亲和力和低亲和力结合，可改善对组蛋白H1实验FRAP数据的解释。为了说明结果，我们使用其中一个有利模型评估核心组蛋白高度乙酰化后组蛋白H1的动力学变化，并得出结论，这种转录后修饰不会显著影响组蛋白H1从弱结合状态到紧密结合状态的转变。
