SUMO as a nuclear hormone receptor effector: New insights into combinatorial transcriptional regulation

Animal development is driven by robust, cell-specific gene expression programs. Understanding mechanistically how a single transcription factor (TF) can govern distinct programs with exquisite precision is a major challenge. We view TFs as signal integrators, taking information from co-regulator interactions, post-translational modifications, other transcription factors, chromatin state, DNA sequence and in some cases, specific noncovalent ligands, to determine the collection of genes regulated by a TF at any given time. Here, we describe a reductionist approach to combinatorial transcriptional regulation, focusing on a single C. elegans TF, the nuclear hormone receptor NHR-25, and a single post-translational modification, SUMO. We suggest that the ratio of sumoylated to unsumoylated NHR-25 could specify a switch-like cell-fate decision during vulval development. Direct examination of this "SUMO ratio" in vivo is challenging and we discuss possible solutions going forward. We also consider how sumoylation of multiple substrates might be coordinated during vulval development. Finally, we note that iteration of this approach could leverage our sumoylation findings to define the roles of other effectors of NHR-25 in the developing vulva and in other tissues.