Abstract
The transcriptional effects of the ovarian hormone progesterone are pleiotropic, and binding to DNA of the nuclear progesterone receptor (PR), a ligand-activated transcription factor, results in diverse outcomes in a range of target tissues. To determine whether distinct patterns of genomic interaction of PR contribute to the cell specificity of the PR transcriptome, we have compared the genomic binding sites for PR in breast cancer cells and immortalized normal breast cells. PR binding was correlated with transcriptional outcome in both cell lines, with 60% of progestin-regulated genes associated with one or more PR binding regions. There was a remarkably low overlap between the PR cistromes of the two cell lines, and a similarly low overlap in transcriptional targets. A conserved PR binding element was identified in PR binding regions from both cell lines, but there were distinct patterns of enrichment of known cofactor binding motifs, with FOXA1 sites over-represented in breast cancer cell binding regions and NF1 and AP-1 motifs uniquely enriched in the immortalized normal line. Downstream analyses suggested that differential cofactor availability may generate these distinct PR cistromes, indicating that cofactor levels may modulate PR specificity. Taken together these data suggest that cell-specificity of PR binding is determined by the coordinated effects of key binding cofactors.
Highlights
Considerable effort has been applied over several decades to understanding the molecular mechanisms of progesterone signalling in target tissues such as the breast and endometrium
Generation of genome-wide progesterone receptor (PR) interaction profiles PR genomic interactions were mapped in T-47D breast cancer cells and in the AB32 cell line: a stable PR expressing clone of the MCF-10A immortalized normal breast cell line
We examined the level of enrichment of motifs for NF1 and AP-1 in PR binding regions associated with genes that lost, gained or conserved progestin regulation when FOXA1 was expressed and found no difference between the groups
Summary
Considerable effort has been applied over several decades to understanding the molecular mechanisms of progesterone signalling in target tissues such as the breast and endometrium. Progesterone regulates transcription via its nuclear receptor (PR), which associates with specific target sites on chromatin. In addition to coregulators and cofactors, which associate with the PR regulatory complex by protein-protein interaction, PR recruits chromatin remodelling factors, which modify local DNA architecture to enhance PR interaction and transcriptional activation [8]. Factors known to be involved in chromatin remodelling at progestin-regulated sites include the SWI/SNF chromatin remodelling complex [8,9] and transcription factor NF1, which cooperates with PR for binding and activation of MMTV [10,11]. In addition to direct interaction with DNA at PREs, PR has been reported to associate with target genes via tethering to other transcription factors, including AP-1, SP1 and Stat3 [18,19,20,21,22]
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