MARS: Novel Mechanisms of Gene Activation through Relief of SUMO-mediated Repression of transcription

The fine-tuned expression of thousands of genes is fundamental to all life processes. The symphony of active and repressed genes must be tightly orchestrated in all cells of the body. Aberrant control is often seen in cancer cells, which is one reason why understanding the orchestration systems is important. Gene control is very sophisticated and there are many layers of regulation. This project focuses on a layer of regulation that until now has attracted limited attention, gene control through Relief of SUMO-mediated Repression of transcription. A small protein called SUMO has been found coupled to many gene regulators restraining their activity. This project addresses the uncoupling of this negative modification and studies its effect on gene control in detail. Our primary focus is SENP1, an enzyme that removes SUMO from target proteins. We have identified several novel interaction partners of SENP1, which are currently under investigation to understand how the SUMO-system plays together with other control systems in the cell, in particular epigenetic control. We have found that one of these novel partners is controlled by the cancer-related gene regulator c-Myb, itself a sensitive target for SUMO modification. The latter opens for a highly interconnected control switch where c-Myb not only controls target genes directly but also the SUMO landscape indirectly. This SENP1 target seems also linked to a novel pioneer function of c-Myb that we recently published. Another connection recently published is a link between the SUMO-system and chromatin remodelling through CHD3, which points to a role of SUMO in the highly interconnected systems of control of transcription and epigenetics.

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Modification of proteins with small ubiquitin-related modifiers (SUMOs) is now established as one of the key regulatory modifications in eukaryotic cells, significantly affecting fundamental nuclear processes such as transcription and chromatin organization. A large number of transcription factors and cofactors are SUMO-modified, which in most cases are associated with repression. One implication of this potent repressive mechanism is that relief of SUMO-mediated repression may represent a significant contribution to gene activation. This derepression is still poorly understood and is the subject of the current proposal. By focusing on targeting of SUMO-proteases, link to chromatin remodeling and role in controlling pioneer transcription factors, we aim to unravel novel mechanisms of gene activation based on the con-trolled relief of SUMO-mediated repression of transcription. We will use the transcription factor c-Myb as model, as we have shown that c-Myb is a sensitive target for SUMOylation, recruiting chromatin re-modelers and having properties suggesting a role as pioneer transcription factor. In addition to the project manager, Odd Stokke Gabrielsen, with broad knowledge of the c-Myb and SUMO field, key collaborators are Ragnhild Eskeland, a young investigator with expertise in epigenet-ics, and an international renowned expert in stem cells and c-Myb biology, Jon Frampton, professor at University of Birmingham.