Dataset Information

Meta-analysis of Chromatin Programming by Steroid Receptors.

ABSTRACT: Transcription factors (TFs) must access chromatin to bind to their response elements and regulate gene expression. A widely accepted model proposes that only a special subset of TFs, pioneer factors, can associate with condensed chromatin and initiate chromatin opening. We previously reported that steroid receptors (SRs), not considered pioneer factors, can assist the binding of an archetypal pioneer, the forkhead box protein 1 (FOXA1), at a subset of receptor-activated enhancers. These findings have been challenged recently, with the suggestion that newly acquired data fully support the prevailing pioneer model. Here, we reexamine our results and confirm the original conclusions. We also analyze and discuss a number of available datasets relevant to chromatin penetration by SRs and find a general consensus supporting our original observations. Hence, we propose that chromatin opening at some sites can be initiated by SRs, with a parallel recruitment of factors often treated as having a unique pioneer function. This Matters Arising paper is in response to Glont et al. (2019), published in Cell Reports.

SUBMITTER: Paakinaho V

PROVIDER: S-EPMC6914262 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Meta-analysis of Chromatin Programming by Steroid Receptors.

Paakinaho Ville V Swinstead Erin E EE Presman Diego M DM Grøntved Lars L Hager Gordon L GL

Cell reports 20190901 13

Transcription factors (TFs) must access chromatin to bind to their response elements and regulate gene expression. A widely accepted model proposes that only a special subset of TFs, pioneer factors, can associate with condensed chromatin and initiate chromatin opening. We previously reported that steroid receptors (SRs), not considered pioneer factors, can assist the binding of an archetypal pioneer, the forkhead box protein 1 (FOXA1), at a subset of receptor-activated enhancers. These findings ...[more]

PMID: 31553919

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Project description:Estradiol and progesterone bind to their respective receptors in the hypothalamus and hippocampus to influence a variety of behavioral and physiological functions, including reproduction and cognition. Work from our lab and others has shown that the nuclear receptor coactivators, steroid receptor coactivator-1 (SRC-1) and SRC-2, are essential for efficient estrogen receptor (ER) and progestin receptor (PR) transcriptional activity in brain and for hormone-dependent behaviors. While the expression of SRC-1 in brain has been studied extensively, little is known about the expression of SRC-2 in brain. In the present studies, we found that SRC-2 was highly expressed throughout the hippocampus, amygdala and hypothalamus, including the medial preoptic area (MPOA), ventral medial nucleus (VMN), arcuate nucleus (ARC), bed nucleus of the stria terminalis, supraoptic nucleus and suprachiasmatic nucleus. In order for coactivators to function with steroid receptors, they must be expressed in the same cells. Indeed, SRC-2 and ER(alpha) were coexpressed in many cells in the MPOA, VMN and ARC, all brain regions known to be involved in female reproductive behavior and physiology. While in vitro studies indicate that SRC-2 physically associates with ER and PR, very little is known about receptor-coactivator interactions in brain. Therefore, we used pull-down assays to test the hypotheses that SRC-2 from hypothalamic and hippocampal tissue physically associate with ER and PR subtypes in a ligand-dependent manner. SRC-2 from both brain regions interacted with ER(alpha) bound to agonist, but not in the absence of ligand or in the presence of the selective ER modulator, tamoxifen. Analysis by mass spectrometry confirmed these ligand-dependent interactions between ER(alpha) and SRC-2 from brain. In dramatic contrast, SRC-2 from brain showed little to no interaction with ERbeta. Interestingly, SRC-2 from both brain regions interacted with PR-B, but not PR-A, in a ligand-dependent manner. Taken together, these findings reveal that SRC-2 is expressed in brain regions known to mediate a variety of steroid-dependent functions. Furthermore, SRC-2 is expressed in many ER(alpha) containing cells in the hypothalamus. Finally, SRC-2 from brain interacts with ER and PR in a subtype-specific manner, which may contribute to the functional differences of these steroid receptor subtypes in brain.

Dataset Information

Meta-analysis of Chromatin Programming by Steroid Receptors.

Publications

Meta-analysis of Chromatin Programming by Steroid Receptors.

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