Biomolecular Condensates in Transcriptional Regulation

Abstract

Transcriptional regulation of gene expression is fundamental in determining cell behavior, identity, and organism development. When dysregulated it can cause disease. Core to transcriptional regulation is the control of RNA polymerase II (RNAPII) activity. The combined activity of DNA regulatory elements, transcription factors and cofactors, and epigenetic chromatin states determine where and when RNAPII transcribes – and thus regulates transcriptional activity. The highly cooperative interactions between components that positively and negatively regulate transcription have been mysterious for decades. However, recent study of biomolecular condensates has reframed our understanding of these cooperative interactions. Condensates are membrane-less compartments that concentrate components involved in the same biochemical processes. This thesis examines the formation and function of condensates that both activate and repress transcription. Transcriptional condensates form at active euchromatic genes to facilitate transcription (Sabari et al., 2018). In contrast, heterochromatin condensates form at transcriptionally silent regions of the genome to repress transcription (Li et al., 2020). Studies presented in this thesis demonstrate that transcriptional and heterochromatin condensates regulate gene expression via the concentration of specific components. Notably, we find that methyl-CpG binding protein 2 (MeCP2) is a key component of heterochromatin condensates. Mutations in MeCP2 cause the neurodevelopmental disorder Rett syndrome, and we link disease-causing mutations in MeCP2 to the disruption of heterochromatin condensate formation and function. These findings implicate condensate disruption in human disease. Our new understanding of condensates demands the development of new therapeutic hypotheses that must be explored in order to improve the lives of patients.