Nuclear receptors (NRs) are key factors regulating fundamental cell fate decisions during organogenesis, growth, homeostatic tissue maintenance and renewal. Through influencing the expression of genes within complex regulatory networks, NRs affect a diverse spectrum of physiological and pathological processes, including differentiation, cellular homeostasis, cancer and metabolic diseases. Prime examples are estrogen-dependent breast cancer and androgen-dependent prostate cancer.
Transcription of NR-regulated genes is a complex, tightly regulated process where distinct NRs, in conjunction with other transcription factors (TFs), the basal transcription machinery and covalent modifications to chromatin, collectively act to regulate gene expression. The major objectives of SYNERGY (Systems approach to gene regulation biology through nuclear receptors) are to characterize the roles of four nuclear receptors (NRs), RNA polymerase II and four histone marks in tumor cells and in normal breast and prostate cells. We will determine NR binding through ChIP-seq; gene expression with RNA-seq and place these datasets in context with DNA methylation and histone marks at multiple time points. These measurements will provide unique temporal datasets that will be used to design and implement computational methods to (i) identify genes regulated by NRs, (ii) infer the mechanisms of NR-triggered gene regulation, and (iii) identify pathways, biological processes and gene regulatory networks that the NR-responsive genes are involved in.
SYNERGY is built upon interactive cycles between experimental (Henk Stunnenberg, Olli A. Jänne, George Reid) and modeling oriented (Sampsa Hautaniemi, Magnus Rattray, Antti Honkela, Genomatix Ltd.) groups. The models will be extensively validated during the project, and the predictions emerging from the models will be used to direct experiments that lead to more comprehensive understanding of gene regulation.
DKFZ Heidelberg, DE