Estrogen receptors α/β exhibit distinct intermolecular interactions to mediate gene regulatory events

Estrogen receptors (ERα and ERβ) are intracellular transcription factors that regulate gene expression when bound by estrogens. Although their roles in cellular functions and the onset of disease are relatively well-documented, their interactions with mitotic chromatin in the context of 'mitotic bookmarking' remain largely unexplored. The current study revealed distinct mechanisms underlying mitotic chromatin retention of ERα and ERβ, emphasizing structural and functional determinants of ER-chromatin association. We further assessed how diverse modulatory ligands impact ER-chromatin interactions during mitosis with potential implications in endocrine therapy.

The study was conducted primarily using live-cell imaging, chromatin immunoprecipitation assays, and site-directed mutagenesis.

We discovered that ERα associates with chromatin in a ligand-dependent manner through a critical RK amino acid stretch in its nuclear localization signal. On the contrary, ERβ binds mitotic chromatin constitutively without ligand involvement. Moreover, ERβ influenced ERα's chromatin association via heterodimeric interactions. Diverse modulatory ligands differentially altered ER dynamics; agonists increased ERα's chromatin binding, whereas antagonists did not. However, only SERMs modulated ERβ's constitutive association with mitotic chromatin. ChIP results indicated that 17β-estradiol-bound ERα and unliganded ERβ associate with their target gene promoters during mitosis, suggesting a role in mitotic bookmarking.

The study advances our understanding of ER-mediated epigenetic regulation and offers a framework for evaluating ER-associated disease states and improving endocrine therapeutic strategies.