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的方法来研究正常和转化造血系统中的干细胞组织。这是我们的目标，以促进更好地了解之间的平衡自我更新和分化的HSC，特别是其控制的表观遗传修饰。为此，我们开发了第一个多尺度的HSC分化的表观遗传调控的计算机模型。我们联合收割机，从而扩展了我们小组开发的两种模型方法;一种基于人工基因组的染色质重塑转录调控模型和一种HSC组织的群体模型。由此产生的模型将能够连接i）组蛋白修饰，ii）DNA甲基化和iii）基因转录的分子现象。此外，使用基于个体的方法，组合模型将允许遵循个体细胞的自我更新和分化动力学，并且将能够模拟HSC群体内的异质性和克隆竞争。我们的研究将提供噪声驱动的干细胞组织的概念的分子解释，并相应地将提高我们的理解不仅HSC，但一般的体干细胞。该模型将适用于体内和体外情况;在后者的情况下，它将特别能够模拟几乎任何培养条件下的克隆扩增。我们将该模型应用于HSC自我更新和分化的实验数据，在稳态条件下和恶性转化。我们专注于AML过程中的髓系分化和失调。我们将表观遗传失调模拟为已知在AML中经常突变的表观遗传调节因子（包括DNMT 3a和IDH 1/2）的功能障碍。我们的模拟研究提供了AML中组蛋白修饰，DNA甲基化和转录的全基因组变化的机制解释-与正常细胞相比。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。与此同时，SPP 1463的不同组的实验结果的整合将促进从造血系统的这种概括性描述到选定AML场景的更具体描述的逐步进展。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，我们专注于DNA去甲基化的协议。通过这种方式，拟议项目将有效地连接SPP 1463的许多项目

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