Long-range transcriptional control of progesterone receptor gene expression.
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.
Bonéy-Montoya
Jamie
J
Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
Ziegler
Yvonne S
YS
Curtis
Carol D
CD
Montoya
Jonathan A
JA
Nardulli
Ann M
AM
D000107:Acetylation / Q000187:drug effects; D045744:Cell Line, Tumor; D002843:Chromatin / Q000737:chemistry; D019295:Computational Biology / Q000379:methods; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D004967:Estrogens / Q000494:pharmacology*; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005786:Gene Expression Regulation; D006657:Histones / Q000378:metabolism; D006801:Humans; D056921:Nuclear Receptor Coactivator 3 / Q000378:metabolism; D009690:Nucleic Acid Conformation; D012333:RNA, Messenger / Q000378:metabolism; D011980:Receptors, Progesterone / Q000235:genetics* / Q000378:metabolism; D020218:Response Elements / Q000235:genetics*; D050052:TRPC Cation Channels / Q000235:genetics / Q000378:metabolism; D000074287:TRPC6 Cation Channel; D013997:Time Factors; D050880:p300-CBP Transcription Factors / Q000378:metabolism; D000099224:p300-CBP-Associated Factor
D002843:Chromatin; D004268:DNA-Binding Proteins; D004958:Estradiol; D047628:Estrogen Receptor alpha; D004967:Estrogens; D051858:Forkhead Transcription Factors; D006657:Histones; D056921:Nuclear Receptor Coactivator 3; D012333:RNA, Messenger; D011980:Receptors, Progesterone; D050052:TRPC Cation Channels; D000074287:TRPC6 Cation Channel; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C486413:FOXF2 protein, human; C117032:TRPC6 protein, human; C538866:NCOA3 protein, human