Impact of chromatin structure on PR signaling: Transition from local to global analysis

Abstract

The progesterone receptor (PR) interacts with chromatin in a highly dynamic manner that requires ongoing chromatin remodeling, interaction with chaparones and activity of the proteasome. Here we discuss dynamic interaction of steroid receptor with chromatin, with special attention not only to PR but also to the glucocorticoid receptor (GR), as these receptors share many similarities regarding interaction with, and remodeling of, chromatin. Both receptors can bind nucleosomal DNA and have accordingly been described as pioneering factors. However recent genomic approaches (ChIP-seq and DHS-seq) show that a large fraction of receptor binding events occur at pre-accessible chromatin. Thus factors which generate and maintain accessible chromatin during development, and in fully differentiated tissue, contribute a major fraction of receptor tissue specificity. In addition, chromosome conformation capture techniques suggest that steroid receptors preferentially sequester within distinct nuclear hubs. We will integrate dynamic studies from single cells and genomic studies from cell populations, and discuss how genomic approaches have reshaped our current understanding of mechanisms that control steroid receptor interaction with chromatin.

Nuclear receptors and chromatin: an inducible couple

“…Accordingly, GR activation using dexamethasone can increase binding of E2-induced ERa at proximal chromatin locations (Voss et al 2011, Miranda et al 2013. Very similar observations were made with regard to the PR (Grøntved & Hager 2012). Furthermore, another recent report has identified local interactions between ERa and LRH1 (Lai et al 2013).…”

Steroid Receptors in the Uterus and Ovary

“…Rather, it is apparent that chromatin exhibits "pre-opened" regions destined to recruit NR. 356 For ER in MCF7, FoxA1 establishes ER and AR accessible regions; for other cells or other NRs this function might be mediated by other "pioneers", such as AP1 for GR. 354 The accessible chromatin regions are co-localized within nuclear "hubs" that seem to optimize frequency of interaction with NR.…”

“…354 The accessible chromatin regions are co-localized within nuclear "hubs" that seem to optimize frequency of interaction with NR. 356 ChIP-seq is also used to locate other molecules involved in chromatin remodeling and transcriptional regulation, and to examine activating or repressive histone modifications or "marks". These maps of relative locations and dynamics of NR and chromatin components greatly enhance our understanding of hormone response mechanisms.…”

What's new in estrogen receptor action in the female reproductive tract

“…ERs bind to thousands of sites within the cellular chromatin, and not all potential EREs in every cell bind ER. Rather, it is apparent that chromatin exhibits “pre-opened” regions destined to recruit ER ( Grontved and Hager 2012 ). For ER in MCF7, FoxA1 can establish ER accessible regions.…”