Non-Overlapping Progesterone Receptor Cistromes Contribute to Cell-Specific Transcriptional Outcomes

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.

[1]  K. Zaret,et al.  Specific interactions of the wing domains of FOXA1 transcription factor with DNA. , 2007, Journal of molecular biology.

[2]  Gratien G. Prefontaine,et al.  Histone Methylation-Dependent Mechanisms Impose Ligand Dependency for Gene Activation by Nuclear Receptors , 2007, Cell.

[3]  B. Tom,et al.  Determination of the transcript profile of human endometrium. , 2003, Molecular human reproduction.

[4]  C. Clarke,et al.  Progestin regulation of cellular proliferation. , 1990, Endocrine reviews.

[5]  Antoine H. F. M. Peters,et al.  LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription , 2005, Nature.

[6]  Damian Roqueiro,et al.  Genome-Wide Progesterone Receptor Binding: Cell Type-Specific and Shared Mechanisms in T47D Breast Cancer Cells and Primary Leiomyoma Cells , 2012, PloS one.

[7]  M. Beato,et al.  Nuclear Factor 1 Synergizes with Progesterone Receptor on the Mouse Mammary Tumor Virus Promoter Wrapped around a Histone H3/H4 Tetramer by Facilitating Access to the Central Hormone-responsive Elements* , 2009, The Journal of Biological Chemistry.

[8]  J. Graham,et al.  Characterization of progesterone receptor A and B expression in human breast cancer. , 1995, Cancer research.

[9]  J. Stamatoyannopoulos,et al.  Chromatin accessibility pre-determines glucocorticoid receptor binding patterns , 2011, Nature Genetics.

[10]  J. Scammell,et al.  Intronic hormone response elements mediate regulation of FKBP5 by progestins and glucocorticoids , 2004, Cell stress & chaperones.

[11]  J. Eeckhoute,et al.  Unique ERalpha cistromes control cell type-specific gene regulation. , 2008, Molecular endocrinology.

[12]  R. Gronostajski,et al.  The Nuclear Factor I (NFI) Gene Family in Mammary Gland Development and Function , 2003, Journal of Mammary Gland Biology and Neoplasia.

[13]  Klaus H. Kaestner,et al.  FOXA1 is an essential determinant of ERα expression and mammary ductal morphogenesis , 2010, Development.

[14]  Cole Trapnell,et al.  Ultrafast and memory-efficient alignment of short DNA sequences to the human genome , 2009, Genome Biology.

[15]  C. Glass,et al.  Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. , 2010, Molecular cell.

[16]  K. Horwitz,et al.  Differential Gene Regulation by the Two Progesterone Receptor Isoforms in Human Breast Cancer Cells* , 2002, The Journal of Biological Chemistry.

[17]  Lucia Altucci,et al.  Estrogens and Progesterone Promote Persistent CCND1 Gene Activation during G1 by Inducing Transcriptional Derepression via c-Jun/c-Fos/Estrogen Receptor (Progesterone Receptor) Complex Assembly to a Distal Regulatory Element and Recruitment of Cyclin D1 to Its Own Gene Promoter , 2004, Molecular and Cellular Biology.

[18]  S. Belikov,et al.  FoxA1 Binding Directs Chromatin Structure and the Functional Response of a Glucocorticoid Receptor-Regulated Promoter , 2009, Molecular and Cellular Biology.

[19]  M. Beato,et al.  Minireview: role of kinases and chromatin remodeling in progesterone signaling to chromatin. , 2010, Molecular endocrinology.

[20]  C. Glass,et al.  Reprogramming Transcription via Distinct Classes of Enhancers Functionally Defined by eRNA , 2011, Nature.

[21]  K. Kaestner,et al.  The Foxa family of transcription factors in development and metabolism , 2006, Cellular and Molecular Life Sciences CMLS.

[22]  Charles Kooperberg,et al.  Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. , 2002, JAMA.

[23]  Clifford A. Meyer,et al.  FoxA1 Translates Epigenetic Signatures into Enhancer-Driven Lineage-Specific Transcription , 2008, Cell.

[24]  X. Liao,et al.  Different DNA contact schemes are used by two winged helix proteins to recognize a DNA binding sequence. , 1997, Nucleic acids research.

[25]  Valerie Beral,et al.  Breast cancer and hormone-replacement therapy in the Million Women Study , 2003, The Lancet.

[26]  J. P. Yang,et al.  Global gene profiling in human endometrium during the window of implantation. , 2002, Endocrinology.

[27]  Clifford A. Meyer,et al.  Genome-wide analysis of estrogen receptor binding sites , 2006, Nature Genetics.

[28]  Wilfred W. Li,et al.  MEME: discovering and analyzing DNA and protein sequence motifs , 2006, Nucleic Acids Res..

[29]  H. Stunnenberg,et al.  ChIP‐Seq of ERα and RNA polymerase II defines genes differentially responding to ligands , 2009, The EMBO journal.

[30]  T. Longacre,et al.  A Correlative Morphologic Study of Human Breast and Endometrium in the Menstrual Cycle , 1986, The American journal of surgical pathology.

[31]  J. Graham,et al.  Physiological action of progesterone in target tissues. , 1997, Endocrine reviews.

[32]  Qian Wang,et al.  A comprehensive view of nuclear receptor cancer cistromes. , 2011, Cancer research.

[33]  M. Mann,et al.  Two Chromatin Remodeling Activities Cooperate during Activation of Hormone Responsive Promoters , 2009, PLoS genetics.

[34]  D. Agard,et al.  Estrogen receptor pathways to AP-1 , 2000, The Journal of Steroid Biochemistry and Molecular Biology.

[35]  R. Shukin,et al.  Determinants of DNA sequence specificity of the androgen, progesterone, and glucocorticoid receptors: evidence for differential steroid receptor response elements. , 1999, Molecular endocrinology.

[36]  C. Watson,et al.  Stat5 as a Target for Regulation by Extracellular Matrix (*) , 1995, The Journal of Biological Chemistry.

[37]  M. Tkach,et al.  Progesterone Receptor Induces ErbB-2 Nuclear Translocation To Promote Breast Cancer Growth via a Novel Transcriptional Effect: ErbB-2 Function as a Coactivator of Stat3 , 2010, Molecular and Cellular Biology.

[38]  J. Mesirov,et al.  GenePattern 2.0 , 2006, Nature Genetics.

[39]  J. Graham,et al.  DNA replication licensing and progenitor numbers are increased by progesterone in normal human breast. , 2009, Endocrinology.

[40]  V. Beral,et al.  Breast Cancer Risk in Relation to the Interval Between Menopause and Starting Hormone Therapy , 2011, Journal of the National Cancer Institute.

[41]  C. Lange,et al.  Progesterone receptor rapid signaling mediates serine 345 phosphorylation and tethering to specificity protein 1 transcription factors. , 2008, Molecular endocrinology.

[42]  B. O’Malley,et al.  Sequence and Characterization of a Coactivator for the Steroid Hormone Receptor Superfamily , 1995, Science.

[43]  K. Byth,et al.  Altered progesterone receptor isoform expression remodels progestin responsiveness of breast cancer cells. , 2005, Molecular endocrinology.

[44]  J. Manson,et al.  Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women. , 2010, JAMA.

[45]  P. Carlsson,et al.  Cloning and characterization of seven human forkhead proteins: binding site specificity and DNA bending. , 1994, The EMBO journal.

[46]  Hao Li,et al.  Cell- and gene-specific regulation of primary target genes by the androgen receptor. , 2007, Genes & development.

[47]  W. Okulicz,et al.  Microarray profiling of progesterone-regulated endometrial genes during the rhesus monkey secretory phase , 2004, Reproductive biology and endocrinology : RB&E.

[48]  Cem Elbi,et al.  Ligand-Specific Dynamics of the Progesterone Receptor in Living Cells and during Chromatin Remodeling In Vitro , 2005, Molecular and Cellular Biology.

[49]  J. V. Miller,et al.  Monoclonal antibodies to human progesterone receptor: characterization by biochemical and immunohistochemical techniques. , 1987, Endocrinology.

[50]  Mark Garton,et al.  Breast cancer and hormone-replacement therapy: the Million Women Study , 2003, The Lancet.

[51]  Abraham P. Fong,et al.  Genome-wide transcription factor binding: beyond direct target regulation. , 2011, Trends in genetics : TIG.

[52]  K. Pienta,et al.  A hierarchical network of transcription factors governs androgen receptor-dependent prostate cancer growth. , 2007, Molecular cell.

[53]  D. Edwards,et al.  The constitution of a progesterone response element. , 1993, Molecular endocrinology.

[54]  M. Beato,et al.  Chromatin Remodeling and Control of Cell Proliferation by Progestins via Cross Talk of Progesterone Receptor with the Estrogen Receptors and Kinase Signaling Pathways , 2006, Annals of the New York Academy of Sciences.

[55]  B. Williams,et al.  Mapping and quantifying mammalian transcriptomes by RNA-Seq , 2008, Nature Methods.

[56]  Neil J. McKenna,et al.  Combinatorial Control of Gene Expression by Nuclear Receptors and Coregulators , 2002, Cell.

[57]  J. Carroll,et al.  FOXA1 is a critical determinant of Estrogen Receptor function and endocrine response , 2010, Nature Genetics.

[58]  B. O’Malley,et al.  Sequential recruitment of steroid receptor coactivator-1 (SRC-1) and p300 enhances progesterone receptor-dependent initiation and reinitiation of transcription from chromatin , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[59]  Philip Machanick,et al.  The value of position-specific priors in motif discovery using MEME , 2010, BMC Bioinformatics.

[60]  N. D. Clarke,et al.  Integrative model of genomic factors for determining binding site selection by estrogen receptor-α , 2010, Molecular systems biology.

[61]  Richard M Myers,et al.  Genomic determination of the glucocorticoid response reveals unexpected mechanisms of gene regulation. , 2009, Genome research.

[62]  M. Tang,et al.  Progesterone receptor (hPR) upregulates the fibronectin promoter activity in human decidual fibroblasts. , 2003, DNA and cell biology.

[63]  J. Graham,et al.  Progesterone action in human tissues: regulation by progesterone receptor (PR) isoform expression, nuclear positioning and coregulator expression , 2009, Nuclear receptor signaling.

[64]  J. Weinstein,et al.  Karyotypic complexity of the NCI-60 drug-screening panel. , 2003, Cancer research.

[65]  Hao Li,et al.  Determinants of Cell- and Gene-Specific Transcriptional Regulation by the Glucocorticoid Receptor , 2007, PLoS genetics.