Steroid Receptors and SUMO Modifications in the Regulation of Gene Networks and Cellular Plasticity
In-depth understanding of the function and the regulation of transcription factors (TFs) is of utmost importance in the understanding how cellular signals, such as steroid hormones, program gene expression and thereby cell physiology. We study steroid receptors, androgen receptor (AR) and glucocorticoid receptor (GR), as our main model TFs. They are ligand/steroid-controlled TFs and important drug targets. These small-molecule drugs inhibit or induce transcription. Targeting of the AR is exploited in prostate cancer therapy. Glucocorticoids are among the key drugs for treating diseases ranging from hematological cancers to inflammatory states.
Transcriptional regulation of gene networks by steroids not only involves binding of their receptors to specific DNA elements, but also critical interaction with coregulator proteins and crosstalk with other TFs. The coregulator proteins often mediate or catalyze post-translational modifications (PTMs), lysine PTMs acetylation and methylation in particular. The PTMs target both TFs and chromatin proteins, eliciting dynamic changes in the TF activity and chromatin structure. SUMOylation, a conserved lysine PTM, has emerged as an important regulatory mechanism in transcription, genomic integrity and cellular homeostasis. It appears to act as an early defence mechanism against protein-damaging stresses and an important regulator of cellular plasticity.
Our research builds on our firm expertise in the steroid signaling and transcriptional regulation and our pioneering work on the SUMOylation of TFs and chromatin.
Our current major goals are to:
- Identify the chromatin-bound proteins associated with the AR and the GR and reveal the role of SUMOylation in these associations.
- Discover novel means to target the AR and GR in castration resistant prostate cancer.
Reveal the chromatin targets and mechanisms by which SUMOylation regulates gene networks and chromatin structure in cellular plasticity.
To address these aims, we will use cutting-edge genome- and proteome-wide tools, including GRO-seq, ChIP-seq, ChIP-SICAP and Turbo-ID proximity labeling, with human prostate cancer cell lines, mesenchymal stem cells and reprogrammable somatic cells as our main model systems.
Scientific and Societal Impact of Research
We anticipate that our systemic studies and studies will provide us with novel leads for targeting steroid receptors. We also believe that our innovative and systematic approaches with multitalented research collaboration will provide us with novel SUMOylation targets and significant discoveries of the mechanisms by which SUMOylation regulates cellular plasticity and homeostasis. The results are likely to have translational potential in regenerative medicine and drug discovery for diseases, such as cancer.
Tiina Jääskeläinen, Einari Niskanen, Raghavendra Mysore, Joanna Lempiäinen, Kaiser Manjur, Kaisa-Mari Vuoti, Merja Räsänen.
Academy of Finland, Sigrid Jusélius Foundation, Finnish Cancer Organisations, UEF Graduate School of Molecular Medicine.
J. Krijgsveld & G. Sigismondo (Heidelberg, Germany), K. Hochedlinger & B. Di Stefano (Boston, USA), C. Libert (Gent, Belgium), A. Pichler (Freiburg, Germany), G.L. Hager (Bethesda, USA), P. Sipilä & M. Poutanen, N. Kotaja (Turku, Finland), L. Sistonen (Turku, Finland), M. Varjosalo, (Helsinki, Finland), M. Malinen (Joensuu, Finland).