Conformation regulation of the X chromosome inactivation center: a model.
Conformation regulation of the X chromosome inactivation center: a model.
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DOI：
10.1371/journal.pcbi.1002229
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发表时间：
2011-10
影响因子：
4.3
通讯作者：
Nicodemi M
中科院分区：
文献类型：
--
作者：
Scialdone A;Cataudella I;Barbieri M;Prisco A;Nicodemi M
X染色体失活(XCI)是一个随机选择的X在雌性细胞中转录沉默的过程。XCI由XIC控制，XIC是X上的一个基因座，包含一系列相互作用的基因和关键的分子因子。然而，建立X的命运的机制，以及相应的XIC架构的替代修改，仍然是神秘的。在这项研究中，通过使用计算机模拟，我们探索了染色质构象出现在其与扩散分子因子的相互作用中的情景。我们的目的是了解在XIC上建立稳定、非随机构象的物理机制，如何可靠地调节复杂的结构变化，以及它们如何导致两个等位基因上的相反结构。特别是，与现有实验数据的比较表明，几个关键的顺式调控区域协调了XIC的组织，并涉及两个主要的分子调控因子。在哺乳动物雌性细胞中，X染色体失活(XCI)是一个重要的过程，在这个过程中，随机选择的一个X被沉默，以补偿相对于雄性X产品的剂量。XCI由X上的一个区域--X失活中心(XIC)控制，该区域在这个过程中经历了一系列的构象改变。然而，这两个XIC暴露在相同的环境中，它们如何获得不同的体系结构尚不清楚。通过分子模型的计算机模拟，我们个体化了一般的物理机制，随机的布朗分子可以组装染色质稳定的结构，可靠地调节构象变化，并在相同的等位基因上建立相反的转换。在对小鼠XIC的案例研究中，我们的分析强调了几个关键调控区域和分子因素的存在。它还预测，例如，与当前的缺失/插入实验相比较的该基因座中的遗传修改的效果。我们描述的物理机制植根于热力学，可能远远超出XCI。
X-Chromosome Inactivation (XCI) is the process whereby one, randomly chosen X becomes transcriptionally silenced in female cells. XCI is governed by the Xic, a locus on the X encompassing an array of genes which interact with each other and with key molecular factors. The mechanism, though, establishing the fate of the X's, and the corresponding alternative modifications of the Xic architecture, is still mysterious. In this study, by use of computer simulations, we explore the scenario where chromatin conformations emerge from its interaction with diffusing molecular factors. Our aim is to understand the physical mechanisms whereby stable, non-random conformations are established on the Xic's, how complex architectural changes are reliably regulated, and how they lead to opposite structures on the two alleles. In particular, comparison against current experimental data indicates that a few key cis-regulatory regions orchestrate the organization of the Xic, and that two major molecular regulators are involved. In mammal female cells X-Chromosome Inactivation (XCI) is the vital process whereby one X, randomly chosen, is silenced to compensate dosage of X products with respect to males. XCI is governed by a region on the X, the X Inactivation Centre (Xic), which undergoes a sequence of conformational modifications during the process. The two Xic are exposed, though, to the same environment, and it is obscure how they attain different architectures. By use of computer simulations of a molecular model, here we individuate general physical mechanisms whereby random Brownian molecules can assemble chromatin stable architectures, reliably regulate conformational changes, and establish opposite transformations on identical alleles. In the case-study of the murine Xic, our analysis highlights the existence of a few key regulatory regions and molecular factors. It also predicts, e.g., the effects of genetic modifications in the locus, which are compared with current deletion/insertion experiments. The physical mechanisms we describe are rooted in thermodynamics and could be relevant well beyond XCI.
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