Phase transitions and gene regulation

Of the dozens of liquid phase membrane-less bodies in the cell, nuclear bodies are particularly interesting, since they directly interact with and regulate the genome (Fig. 1). Our work to date has focused on nucleoli, the most prominent nuclear body associated with the biogenesis of ribosomes, the protein translation machinery (see e.g. Weber Curr Biol 2015, Berry PNAS 2015, Feric Cell 2016). We are also interested in nuclear bodies associated with the active transcription and processing of other genes, which are associated with condensates such as transcriptional hubs, Cajal bodies, and nuclear speckles. The molecular players underlying phase separation of these structures typically include intrinsically disordered proteins/regions (IDPs/IDRs), and their oligomerization, as well as interactions with RNA. Moreover, DNA is not only restructured in response to RNA/protein-driven phase separation, but itself may phase separate to give rise to higher order genome architecture. The interplay of these effects, and the impacts on biological function, are still largely unclear, and represents a major uncharted universe of non-covalent epigenetic regulation and dynamics. We have various collaborators involved in this work, many of whom are associated with the NIH 4D Nucleome Consortium.