Endocrine examples of phase separation in biology.

Abstract

Over the past 15 years, groundbreaking discoveries have reshaped our understanding of how biomolecules are organized in space and time within cells, revealing that many cellular compartments are separated from their surroundings not by membranes, but by physical forces arising from unique interactions among their biomolecular components. These interactions drive the compartmentalization of biomolecules through liquid-liquid phase separation (LLPS) into dynamic droplets, which can further stabilize through liquid-gel phase separation (LGPS). Phase separation plays essential roles across diverse biological systems, including the endocrine system, where it impacts the function on steroid hormone receptors (SHRs). SHRs are a family of nuclear receptors that transduce steroid signals to regulate transcription of thousands of genes, thereby supporting endocrine homeostasis and contributing to diseases when dysregulated. During gene activation, SHRs form high-density clusters at promoters and enhancers. This minireview summarizes recent literature indicating that these clusters function as transcriptional condensates, where phase separation of SHRs and coregulators mediates chromatin remodeling and enhanced transcription. We also discuss hypotheses suggesting that SHR-driven LLPS at gene loci contributes to hormone therapy resistance, while a transition to LGPS causes reduced hormone responsiveness. Finally, advancements in SHR condensate-modifying drugs to create new therapeutic options for hormone therapy-resistant cancers are highlighted. Overall, emerging evidence on the phase properties of SHR condensates is transforming our understanding of the endocrine regulation and unleashing novel intervention strategies beyond targeting individual proteins.