Dynamics of chromatin accessibility and long-range interactions in response to glucocorticoid pulsing

Časopis: GENOME RESEARCH 25, 845-857
Autoři: Stavreva, DA., Coulon, A., Baek, S., Sung, MH., John, S., Stixova, L., Tesikova, M., Hakim, O., Miranda, T., Hawkins, M., Stamatoyannopoulos, JA., Chow, CC., Hager, GL.
Rok: 2015


Although physiological steroid levels are often pulsatile (ultradian), the genomic effects of this pulsatility are poorly understood. By utilizing glucocorticoid receptor (GR) signaling as a model system, we uncovered striking spatiotemporal relationships between receptor loading, lifetimes of the DNase I hypersensitivity sites (DHSs), long-range interactions, and gene regulation. We found that hormone-induced DHSs were enriched within +/- 50 kb of GR-responsive genes and displayed a broad spectrum of lifetimes upon hormone withdrawal. These lifetimes dictate the strength of the DHS interactions with gene targets and contribute to gene regulation from a distance. Our results demonstrate that pulsatile and constant hormone stimulations induce unique, treatment-specific patterns of gene and regulatory element activation. These modes of activation have implications for corticosteroid function in vivo and for steroid therapies in various clinical settings.