Epigenetic function of RUNX1 with PRMT6 in normal and aberrant myeloid differentiation

• Applicant: Professor Dr. Jörn Lausen
• Subject Area: Hematology, Oncology
• Term: from 2010 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 171411205

The transcription factor RUNX1 (AML1, acute myeloid leukemia 1) is crucial for the development of definitive hematopoietic stem cells (HSC). RUNX1 activity is often altered in human myeloid leukemia by mutation, deletion and chromosomal translocation. During normal hematopoietic differentiation the recruitment of chromatin modifying cofactors by RUNX1 leads to adjustments of the chromatin structure and also mediates epigenetic changes of gene expression. This epigenetic function of RUNX1 is disturbed in leukemia. We could show that RUNX1 interacts with the protein arginine methyltransferase 6 (PRMT6), which mediates the repressive H3R2me2a histone modification mark. We demonstrated that RUNX1 and PRMT6 are in a repressive epigenetic complex on a subset of target genes in hematopoietic progenitor cells. Based on these results, we want to identify common RUNX1/PRMT6 target genes genome wide by ChIP-Seq and relate RUNX1/PRMT6 occupancy to epigenetic histone marks. Furthermore, we want to decipher the mechanisms of RUNX cofactor exchange during differentiation and uncover the resulting epigenetic changes. Concomitantly, we will study the specific contribution of PRMT6 to RUNX1 dependent epigenetic functions and study the dependence of PRMT6 activity on cofactor recruitment and downstream histone modification marks. Additionally, we collected data, which hint towards an influence of PRMT6 on cell growth, which might be mediated by a direct influence of RUNX1/PRMT6 on growth inhibitory target genes. For this reason we want to evaluate the potential of PRMT6 inhibitors as an epigenetic drug, which acts growth inhibitory. The normal function of RUNX1 can be altered by mutations leading to leukemia, a prominent example is the chromosomal translocation t(8;21) leading to the RUNX1-ETO fusion protein. We want to examine if RUNX1-ETO can interfere with the epigenetic RUNX1/PRMT6 complex and this way contributes to deregulated epigenetic marks, which contribute to leukemia.

• DFG Programme: Priority Programmes
• Subproject of: SPP 1463: Epigenetic Regulation of Normal Hematopoiesis and its Dysregulation in Myeloid Neoplasia
• Participating Persons: Professor Dr. Halvard Bönig; Professor Dr. Manfred Jung