Focus of research
Our focus of research is on the cancer-related, hematopoietic transcription factor, c-Myb (see illustration). As a proto-oncogene c-myb can undergo oncogenic activation, and myb was among the first retroviral oncogenes identified. Recently, c-Myb has gained renewed interest due to its role in regulating stem-progenitor cell homeostasis and its association with human leukaemogenesis. MYB can be activated by inappropriate expression, structural alteration and/or genomic rearrangements.
We believe that it is important to unravel the molecular mechanisms of human c-Myb action, given its key role in hematopoiesis and leukaemogenesis. Despite being an “old” oncogene, our understanding of molecular mechanisms controlling c-Myb function remains incomplete. Our focus is on how the activity of the factor seems to be tightly controlled by various mechanisms involving SUMO-modification and cofactor interaction, leading to chromatin modulation and target gene activation, and how these are perturbed during oncogenic activation.Hence, our on-going research is directed towards four main objectives:
- Defining molecular functions of novel coactivators of c-Myb.
- Unravelling mechanisms of PTM-mediated control of c-Myb activity, focusing on SUMOylation and phosphorylation.
- Investigate how c-Myb through PTMs and cofactor recruitment establishes epigenetic signature(s).
- Identifying novel and robust target genes of c-Myb.
The question of how these mechanism is affected by, or contribute to, oncogenic activation runs as a thread through the four objectives.
Sub-projects
I. Defining molecular functions of novel coactivators of c-Myb
Objective:To identify a set of c-Myb interacting proteins and through studies of their mode of action, alone and in cooperation with c-Myb, to shed light on the function of c-Myb. This line of research currently focuses on:
- The chromatin remodelling factor Mi2α
- The nuclear FLASH protein
- The nuclear kinase HIPK1
- Proteins interacting with FLASH and c-Myb
The studies follow a common framework: interaction → function → mechanism
II. Defining the molecular functions of PTMs of c-Myb
Objective: Unravelling mechanisms of SUMO-mediated control of c-Myb activity, comprising how oncogenic activation affects these mechanisms. This includes SUMO-conjugation, SUMO-binding and SUMO-directed posttranslational modifications (PTMs).
III. Investigate how c-Myb induce epigenetic signatures
Objective: Studies of Myb-induced epigenetics. To obtain a global pattern of c-Myb occupancy in the genome of hematopoietic cells using ChIP chip. Define the Myb-induced epigenetic imprint on a gene regulated by c-Myb. Study the interaction of c-Myb with histones and histone modification enzymes to understand the mechanism of the epigenetic role of c-Myb.
IV. Identifying novel and robust target genes of c-Myb
Objective: Defining novel target genes activated by c-Myb. To identify a global pattern of genes being dependent on c-Myb for their efficient expression. From this pattern, to extract subsets of functions influenced by c-Myb. Define a subset of 3-5 novel target genes strongly regulated by c-Myb for use in functional analyses of c-Myb.