Project Details
Projekt
Computational model of epigenetic regulation of myeloid differentiation during homoeostasis and malignant transformation
Applicants
Dr. Jörg Galle; Professor Dr. Markus Löffler
Subject Area
Hematology, Oncology
Term
from 2014 to 2017
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 248215668
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
DFG Programme
Priority Programmes
