Silvina Nacht, A.Ferrari, RobertoZaurin, RoserScabia, ValentinaCarbonell-Caballero, JoseLe Dily, FrancoisQuilez, JavierLeopoldi, AlexandraBrisken, CathrinBeato, MiguelVicent, Guillermo P.2019-10-032019-10-032019-10-032019-09-1610.15252/embj.2018101426https://infoscience.epfl.ch/handle/20.500.14299/161792WOS:000486204200008Steroid hormones are key gene regulators in breast cancer cells. While estrogens stimulate cell proliferation, progestins activate a single cell cycle followed by proliferation arrest. Here, we use biochemical and genome-wide approaches to show that progestins achieve this effect via a functional crosstalk with C/EBP alpha. Using ChIP-seq, we identify around 1,000 sites where C/EBP alpha binding precedes and helps binding of progesterone receptor (PR) in response to hormone. These regions exhibit epigenetic marks of active enhancers, and C/EBP alpha maintains an open chromatin conformation that facilitates loading of ligand-activated PR. Prior to hormone exposure, C/EBP alpha favors promoter-enhancer contacts that assure hormonal regulation of key genes involved in cell proliferation by facilitating binding of RAD21, YY1, and the Mediator complex. Knockdown of C/EBP alpha disrupts enhancer-promoter contacts and decreases the presence of these architectural proteins, highlighting its key role in 3D chromatin looping. Thus, C/EBP alpha fulfills a previously unknown function as a potential growth modulator in hormone-dependent breast cancer.Biochemistry & Molecular BiologyCell BiologyBiochemistry & Molecular BiologyCell Biologybreast cancerc/ebp alphacell proliferationhormone-dependent gene regulationprogesterone receptorbinding-protein-alphahepatocellular carcinomasregulated expressiontumor-suppressormammary-glandchromatintranscriptionbetageneproliferationtext::journal::journal article::research article