Mammalian cells exhibit a precise gene regulation process, during which enhancers play critical roles in mediating rapid gene activation in response to different signals. Indeed, much of our knowledge about gene transcriptional control comes from the long-standing investigation of the actions of nuclear receptors, well exemplified by estrogen 17?-estradiol (E2)-dependent activation of transcriptional programs. This program is controlled virtually entirely by activation of a cohort of ~1000 robustly activated ER?-bound enhancers. Under physiological conditions, many signals are pulsatile, including ligands for nuclear receptors such as ER?, representing a continuum from transient, acute stimulation to chronic stimulation. We have found that the acute 17?-estradiol (E2)-dependent activation of functional enhancers requires assembly of an eRNA-dependent ribonucleoprotein (eRNP) complex, referred to as the MegaTrans complex. A transformative, newly emerging concept, to which we are pleased to have contributed, is that acute signal of ligand-dependent activation of target enhancers causes them to form an RNA-protein condensate, with features of phase separation, that results in cooperative activation of other homotypic enhancers separated by multiple TADs and, even in other chromosomes. In contrast, chronic signal/ligand activation results in loss of the dynamic RNP condensate at the enhancers, loss of induced proximity of homotypic enhancers observed with acute activation, with enhancer activation function now confined to the nearby cognate target gene promoters. We will use global genomic, proteomic, and real time, single nucleus approaches, with appropriate informatics, to examine the patterns of enhancer activation, potential interactions in acute vs chronic ligand-dependent activation, relationship to localization in phase-separated subnuclear architectural structures and patterns of movement by single molecule imaging. Our goal is to provide a paradigm-shifting insight into ligand/hormone-regulated transcriptional programs, based on this multidisciplinary approach.
Our data suggest that acute signal or ligand-dependent activation of target enhancers causes them to form an RNA-protein condensate, with features of phase separation, resulting in in induced proximity and cooperative activation of other homotypic enhancers, although separated by multiple TADs and, potentially, even in other chromosomes. In contrast, chronic signal/ligand activation results in loss of the dynamic RNP condensate at the enhancers, loss of induced proximity of homotypic enhancers observed with acute activation, with enhancer activation function now confined to the nearby cognate target gene promoters. We will use global genomic, proteomic, and real time, single nucleus approaches with the goal of providing a paradigm-shifting insight into hormone-regulated transcriptional programs.
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