A Set of Accessible Enhancers Enables the Initial Response of Breast Cancer Cells to Physiological Progestin Concentrations

Overview

Journal Nucleic Acids Res

Publisher Oxford University Press

Specialty Biochemistry

Date 2021 Dec 1

PMID 34850111

Citations 11

Authors

Roser Zaurin

Roberto Ferrari

Ana Silvina Nacht

Jose Carbonell

Francois Le Dily

Jofre Font-Mateu

Lara Isabel de Llobet Cucalon

Enrique Vidal

Antonios Lioutas

Miguel Beato

Guillermo P Vicent

Affiliations

Soon will be listed here.

Abstract

Here, we report that in T47D breast cancer cells 50 pM progestin is sufficient to activate cell cycle entry and the progesterone gene expression program. At this concentration, equivalent to the progesterone blood levels found around the menopause, progesterone receptor (PR) binds only to 2800 genomic sites, which are accessible to ATAC cleavage prior to hormone exposure. These highly accessible sites (HAs) are surrounded by well-organized nucleosomes and exhibit breast enhancer features, including estrogen receptor alpha (ERα), higher FOXA1 and BRD4 (bromodomain containing 4) occupancy. Although HAs are enriched in RAD21 and CTCF, PR binding is the driving force for the most robust interactions with hormone-regulated genes. HAs show higher frequency of 3D contacts among themselves than with other PR binding sites, indicating colocalization in similar compartments. Gene regulation via HAs is independent of classical coregulators and ATP-activated remodelers, relying mainly on MAP kinase activation that enables PR nuclear engagement. HAs are also preferentially occupied by PR and ERα in breast cancer xenografts derived from MCF-7 cells as well as from patients, indicating their potential usefulness as targets for therapeutic intervention.

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References

Pierson-Mullany L, Lange C . Phosphorylation of progesterone receptor serine 400 mediates ligand-independent transcriptional activity in response to activation of cyclin-dependent protein kinase 2. Mol Cell Biol. 2004; 24(24):10542-57. PMC: 533997. DOI: 10.1128/MCB.24.24.10542-10557.2004. View

Lieberman-Aiden E, van Berkum N, Williams L, Imakaev M, Ragoczy T, Telling A . Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science. 2009; 326(5950):289-93. PMC: 2858594. DOI: 10.1126/science.1181369. View

Musgrove E, Swarbrick A, Lee C, CORNISH A, Sutherland R . Mechanisms of cyclin-dependent kinase inactivation by progestins. Mol Cell Biol. 1998; 18(4):1812-25. PMC: 121411. DOI: 10.1128/MCB.18.4.1812. View

Buenrostro J, Giresi P, Zaba L, Chang H, Greenleaf W . Transposition of native chromatin for fast and sensitive epigenomic profiling of open chromatin, DNA-binding proteins and nucleosome position. Nat Methods. 2013; 10(12):1213-8. PMC: 3959825. DOI: 10.1038/nmeth.2688. View

Mohammed H, Taylor C, Brown G, Papachristou E, Carroll J, DSantos C . Rapid immunoprecipitation mass spectrometry of endogenous proteins (RIME) for analysis of chromatin complexes. Nat Protoc. 2016; 11(2):316-26. DOI: 10.1038/nprot.2016.020. View

Migliaccio A, Di Domenico M, Castoria G, De Falco A, Bontempo P, Nola E . Tyrosine kinase/p21ras/MAP-kinase pathway activation by estradiol-receptor complex in MCF-7 cells. EMBO J. 1996; 15(6):1292-300. PMC: 450032. View

Owen G, Richer J, Tung L, Takimoto G, Horwitz K . Progesterone regulates transcription of the p21(WAF1) cyclin- dependent kinase inhibitor gene through Sp1 and CBP/p300. J Biol Chem. 1998; 273(17):10696-701. DOI: 10.1074/jbc.273.17.10696. View

Beato M, Herrlich P, Schutz G . Steroid hormone receptors: many actors in search of a plot. Cell. 1995; 83(6):851-7. DOI: 10.1016/0092-8674(95)90201-5. View

Vicent G, Nacht A, Zaurin R, Ballare C, Clausell J, Beato M . Minireview: role of kinases and chromatin remodeling in progesterone signaling to chromatin. Mol Endocrinol. 2010; 24(11):2088-98. PMC: 5417384. DOI: 10.1210/me.2010-0027. View

10.

Sabari B, DallAgnese A, Boija A, Klein I, Coffey E, Shrinivas K . Coactivator condensation at super-enhancers links phase separation and gene control. Science. 2018; 361(6400). PMC: 6092193. DOI: 10.1126/science.aar3958. View

11.

Le Dily F, Vidal E, Cuartero Y, Quilez J, Nacht A, Vicent G . Hormone-control regions mediate steroid receptor-dependent genome organization. Genome Res. 2018; 29(1):29-39. PMC: 6314164. DOI: 10.1101/gr.243824.118. View

12.

Stevens T, Lando D, Basu S, Atkinson L, Cao Y, Lee S . 3D structures of individual mammalian genomes studied by single-cell Hi-C. Nature. 2017; 544(7648):59-64. PMC: 5385134. DOI: 10.1038/nature21429. View

13.

Pang H, Rowan B, Al-Dhaheri M, Faber L . Epidermal growth factor suppresses induction by progestin of the adhesion protein desmoplakin in T47D breast cancer cells. Breast Cancer Res. 2004; 6(3):R239-45. PMC: 400677. DOI: 10.1186/bcr780. View

14.

Meuleman W, Muratov A, Rynes E, Halow J, Lee K, Bates D . Index and biological spectrum of human DNase I hypersensitive sites. Nature. 2020; 584(7820):244-251. PMC: 7422677. DOI: 10.1038/s41586-020-2559-3. View

15.

Liao Y, Wang J, Jaehnig E, Shi Z, Zhang B . WebGestalt 2019: gene set analysis toolkit with revamped UIs and APIs. Nucleic Acids Res. 2019; 47(W1):W199-W205. PMC: 6602449. DOI: 10.1093/nar/gkz401. View

16.

Jiang Y, Qian F, Bai X, Liu Y, Wang Q, Ai B . SEdb: a comprehensive human super-enhancer database. Nucleic Acids Res. 2018; 47(D1):D235-D243. PMC: 6323980. DOI: 10.1093/nar/gky1025. View

17.

Qiu M, Olsen A, Faivre E, Horwitz K, Lange C . Mitogen-activated protein kinase regulates nuclear association of human progesterone receptors. Mol Endocrinol. 2003; 17(4):628-42. DOI: 10.1210/me.2002-0378. View

18.

Gevry N, Hardy S, Jacques P, Laflamme L, Svotelis A, Robert F . Histone H2A.Z is essential for estrogen receptor signaling. Genes Dev. 2009; 23(13):1522-33. PMC: 2704467. DOI: 10.1101/gad.1787109. View

19.

Mumbach M, Rubin A, Flynn R, Dai C, Khavari P, Greenleaf W . HiChIP: efficient and sensitive analysis of protein-directed genome architecture. Nat Methods. 2016; 13(11):919-922. PMC: 5501173. DOI: 10.1038/nmeth.3999. View

20.

Beagrie R, Scialdone A, Schueler M, Kraemer D, Chotalia M, Xie S . Complex multi-enhancer contacts captured by genome architecture mapping. Nature. 2017; 543(7646):519-524. PMC: 5366070. DOI: 10.1038/nature21411. View