Long-Range Transcriptional Control of Progesterone Receptor Gene Expression

Abstract

Estrogen receptor alpha (ERalpha) binds to specific target DNA sequences, estrogen response elements (EREs), to regulate estrogen-responsive gene expression. The progesterone receptor (PR) gene has been used extensively as a marker of estrogen responsiveness. Although we previously identified cis elements within 1 kb of the PR-B transcription start site that are associated with ERalpha and help to confer estrogen responsiveness, the identification of ERalpha binding sites far removed from the transcription start site suggested that long-range regulation of this gene may occur. We now show that eight regions of the PR gene from 311 kb upstream to 4 kb downstream of the PR-B transcription start site interact with ERalpha and that coactivator proteins and acetylated histones are selectively associated with these gene regions. Specific PR gene regions confer estrogen responsiveness to a heterologous reporter plasmid, and mutation of EREs within these regions diminishes estrogen-induced transactivation. Importantly, chromosome conformation capture assays reveal ERalpha- and ligand-dependent interactions between proximal and distal PR gene regions. Taken together, our studies suggest that distal regions of the PR gene participate in the dynamic regulation of this gene and that the coordinated action of proximal and distal PR gene regions allows cells to respond to changes in hormone levels with extraordinary versatility and sensitivity.

Impact of Thyroid Hormones on Estrogen Receptor α-Dependent Transcriptional Mechanisms in Ventromedial Hypothalamus and Preoptic Area

“…2). Two enhancer sites containing EREs (Enh 1 and Enh 3), all homologous to the enhancer sites characterized by BoneyMontoya et al [40] in the MCF-7 cell line, exhibited E2-increased ERα binding in the VMH and POA ( fig. 4 b).…”

“…6 a). In the Hypo group, the ability of E2 to induce ERα association to the [40] . Black diamonds denote conserved ERE sites between human and mouse enhancer sequences.…”

“…Because the consensus DNA sequences bound by ER and TR are very similar [26] , we hypothesized that competitive binding of TRα to the 5 ′ end of a consensus ERE could inhibit ER transactivation and the subsequent gene transcription of mouse Pgr and Oxtr . ERα has been shown not to bind within the promoter region of the human Pgr gene but to be recruited to enhancer sequences as far as 300 kb upstream of the TSS [40] . We were not able to observe ERα recruitment to the four proximal Pgr promoter sites analyzed (online suppl.…”

“…Nonetheless, an ERE half site within the PgR-A promoter was described and found to be conserved in mouse, rat, and human species [36][37][38] . Recently, several ERα binding sites were identified far removed from the PgR-B TSS, suggesting a long-range regulation of this gene [39,40] .…”

Resolvin D2 Supports MCF-7 Cell Proliferation via Activation of Estrogen Receptor

“…Having demonstrated that RvD2 increases ERE-SEAP activity, we then ascertained whether it modulates the transcription of estrogen-responsive genes. Growth regulated by estrogen in breast cancer 1 (GREB1) and progesterone receptor are considered markers of estrogen responsiveness (Rae et al, 2005;Bonéy-Montoya et al, 2010). RvD2 significantly increased GREB1 and progesterone receptor mRNA levels in MCF-7 cells (Fig.…”