Genome-wide studies of nuclear receptors in cell fate decisions

• Emphasis on the retinoic acid receptor system.
• Gene expression signatures of NRs.
• Historical steps leading to the ultimate genome-wide identification of NR binding sites.
• New integrative approaches to reconstruct the dynamic regulatory events induced by NR-signaling.
• Novel directions that are currently explored to study of NR-driven cell fate transitions.

Nuclear receptors (NRs) are important mediators of the information encoded in the chemical structure of its corresponding ligand, as they interpret such information in the context of the cell identity and physiological status and convert it into sequential transcription regulatory events. At the cell level this can result in temporally coordinated processes such as cell fate transitions, which comprise the regulation of a plethora of gene programs including among others regulation of cell proliferation, metabolism and specific functionalities that are acquired by the differentiated cell. While both the early steps of nuclear receptor function and their impact on animal/organ physiology is rather well understood, little is known about the dynamic gene networks that ultimately cause a particular (cell) physiological phenomenon induced by the cognate NR ligand/hormone.Thanks to advances in massive parallel sequencing and bioinformatics analyses of genome-wide data sets, time has come for the development of NR systems biology. Indeed it is now possible to integrate global transcription factor binding, epigenetic chromatin histone and DNA modification patterns with transcriptomes and 3-dimensional chromatin structures, extract decision points in temporal studies and decipher the temporal control of gene networks that are the ultimate genetic readouts of NR ligand-induced physiological phenomena. In this review we will summarize the chronology of the development of increasingly larger data sets for NR action, with a particular focus on studies performed with the RAR/RXR nuclear receptor family, and discuss the present attempts to integrate a multitude of genome-wide data sets in the ultimate context of the temporal 3-dimensional chromatin structure.