Computational model of epigenetic regulation of myeloid differentiation during homoeostasis and malignant transformation

在拟议的项目中，我们将使用系统生物学方法来研究正常和转化的造血系统中的干细胞组织。我们的目标是帮助更好地了解造血干细胞的自我更新和分化之间的平衡，特别是表观遗传修饰物对其控制。为此，我们开发了首个HSC分化表观遗传调控的多尺度计算机模型。我们结合并扩展了我们小组开发的两种模型方法：基于人工基因组的染色质重塑转录调控模型和HSC组织的群体模型。由此产生的模型将能够将i)组蛋白修饰、ii)DNA甲基化和iii)基因转录的分子现象联系起来。此外，使用基于个体的方法，组合模型将允许跟踪单个细胞的自我更新和分化动态，并将能够模拟HSC群体内的异质性和克隆竞争。我们的研究将为噪声驱动的干细胞组织的概念提供分子解释，并相应地不仅将提高我们对HSCs的理解，而且将提高我们对一般体细胞干细胞的理解。该模型将适用于体内和体外的情况；在后者的情况下，它将特别能够模拟在虚拟的任何培养条件下的克隆扩张。我们将该模型应用于HSC在稳态条件下的自我更新和分化以及随后的恶性转化的实验数据。我们关注急性髓系白血病过程中的髓系分化和去调节。我们将表观遗传去调控模拟为已知在AML中频繁突变的表观遗传调节因子的功能障碍，包括DNMT3a和IDH1/2。我们的模拟研究提供了与正常细胞相比，AML全基因组组蛋白修饰、DNA甲基化和转录变化的机制解释。基于这些结果，我们将根据系统中存在的特定突变来确定疾病进展的一般动力学。同时，SPP1463不同组的实验结果的整合将促进从对造血系统的这种概括性描述到对选定AML场景的更具体描述的逐步进步。拟议项目的最终目标是将开发的模型应用于AML亚型的表观遗传干预策略，并支持其优化。在这里，我们重点介绍DNA去甲基化的方案。这样，拟议的项目将有效地将SPP1463的许多项目联系起来

In the proposed project we will use a systems biological approach to investigate stem cell organization within the normal and transformed hematopoietic system. It is our objective to contribute to a better understanding of the balance between self-renewal and differentiation of HSCs, in particular of its control by epigenetic modifiers. For this purpose we develop the first multi-scale computer model of epigenetic regulation of HSC differentiation. We combine and thereby extend two model approaches developed in our group; an artificial genome-based model of transcriptional regulation by chromatin remodeling and a population model of HSC organization. The resulting model will be capable of linking the molecular phenomena of i) histone modification, ii) DNA methylation and iii) gene transcription. Moreover, using an individual-based approach the combined model will allow following the self-renewal and differentiation dynamics of individual cells and will enable simulation of heterogeneity and clonal competition within HSC populations. Our studies will provide a molecular interpretation of the concept of noise-driven stem cell organization and accordingly will improve our understanding not only of HSCs but of somatic stem cells in general. The model will be applicable to both in vivo and in vitro scenarios; in case of the latter it will in particular enable simulation of clonal expansion under virtual any culture condition. We apply the model to experimental data on HSC self-renewal and differentiation under homeostatic conditions and following malignant transformation. We focus on myeloid differentiation and deregulation in course of AML. We simulate epigenetic deregulation as a dysfunction of epigenetic regulators known to be frequently mutated in AML including DNMT3a and IDH1/2. Our simulation studies provide a mechanistic explanation of genome-wide changes of histone modification, DNA methylation and transcription in AML- compared to normal cells. Based on these results we will identify general dynamics of disease progression depending on the particular mutations present in the system. In parallel, the integration of experimental results of different groups of the SPP1463 will foster a step by step progress from such a generalized description of the hematopoietic system to a more specific description of selected AML scenarios. The ultimate goal of the proposed project is to apply the developed model to epigenetic intervention strategies in AML subtypes and to support their optimization. Here, we focus on protocols of DNA de-methylation. In this way the proposed project will effectively link many of the projects of the SPP1463