Project Details
Projekt
Functional analysis of KDM6A histone demethylase in the regulation of HSC development and in leukemogenesis
Applicants
Privatdozent Dr. Matthias Becker; Professor Dr. Albrecht M. Müller (†)
Subject Area
Hematology, Oncology
Term
from 2010 to 2020
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 171631044
The multiple cell lineages of the hematopoietic system are continuously regenerated by hematopoietic stem cells (HSCs). While a stable pool of HSCs is maintained by self-renewal, multipotent HSCs continuously differentiate to produce a large number of myelo/erythroid and lymphoid cell types. For the execution of coordinated self-renewal and differentiation the establishment and maintenance of specific gene expression programs is required. Lineage-specific histone methylation patterns are linked to the regulation of hematopoietic expression programs. The underlying histone methyl transferase activities are mediated by multiprotein complexes with opposing functions that belong to the polycomb- and trithorax group, respectively. Recently a histone H3K27me3-specific histone demethylase (KDM6A, alias UTX) has been identified as part of the trithorax complexes MLL2/3. Our own work performed during the first funding period of the SPP1463 and the work of other labs suggests that KDM6A plays an important role during early meso/hematopoietic differentiation and during adult hematopoiesis. Further analyses identified KDM6A as frequently mutated in human MDS/AML. In the current proposal we project to analyze the genome-wide binding of KMD6A during ES cell hematopoiesis. As KDM6A may fulfill demethylase independent functions during hematopoiesis we will specifically analyze to what extend the KDM6A distribution can be correlated to H3K27me3 pattern. Further we plan to identify novel domains in KDM6A and putative interacting proteins that mediate putative KDM6A demethylase independent function(s). Finally we will address the genomic network of KDM6A during leukemogenesis in a leukemia mouse model. We expect this analysis to provide new mechanistic insights into the regulatory circuitry of histone methylation that is key for HSC development and leukemogenesis.
DFG Programme
Priority Programmes
