Gene Regulation, Stems Cells and Cancer

Chromatin and Gene Expression

Group Structure

Miguel Beato
Guillermo Vicent
François Le Dily, Priyanka Sharma, Gaetano Verde, Michael Wierer (till 30 Jan), Roni Wright, Roser Zaurin (Jan-Aug)
Andy Pohl, Gireesh Bogu (since August, co-mentored with M. Marti-Renom)
Jofre Font Mateu, A. Silvina Nacht, Daniel Soronellas (bioinformatics)
Florence Cere, student Toulouse (Jun-Aug), Viviana Vastolo, PhD Napoli (Aug), Maria Florencia Ogara, PhD Buenos Aires (Sept-Nov)


The group explores how eukaryotic cells respond to external cues, in particular how signals are transduced to the nucleus to modulate chromatin structure and gene expression. Steroid hormones signal to chromatin via binding of their intracellular receptors. A fraction of these receptors is attached to the cell membrane where they crosstalk with kinase signalling pathways, which ultimately facilitate the interaction of receptors with the target sites in nucleosomes and the subsequent chromatin remodelling. The unliganded hormone receptor maintained repressed genes that will be activated by hormone. The hormone initiates two consecutive cycles of remodelling involving kinases; PARP1, histone modifying enzymes and ATP-dependent complexes lead to sequential displacement of histones H1 and H2A/H2B. We are now using antibody arrays and phosphoproteomics to explore the time kinetics of the complete signalling network. Our final aim is to integrate this network with the changes in the topological organization of chromatin that modulate the transcriptional response. In addition we are measuring the energetic requirements of the extensive changes in chromatin dynamics and function. Nodes of the hormonal signalling network and the energy providers for reprogramming gene networks could be targeted for the combinatorial control of cancer cell proliferation.

Research Projects

  • Global analysis of chromatin structure and dynamics during hormonal gene regulation
    G. Bogu, F. Le Dily, S. Nacht, A. Pohl, P. Sharma, D. Soronellas, G. Verde, G. Vicent, R. Wright, R. Zaurin
    Before progestin (Pg) addition to T47D cells, Progesterone Receptor binding sites (PRbs) of genes that will be activated by Pg are partly occupied by unliganded PR associated with a repressive complex containing HP1γ, LSD1, HDACs, KDM5B, COREST and an lncRNA called SRA (Vicent et al., 2013). Upon Pg treatment, the repressive complex is replaced by an activating complex (Vicent et al., PLoS Genetics 2009) (Fig. 1). The density of MNase reads at PRbs decreases significantly after hormone treatment as a consequence of nucleosome remodelling involving histone H1 and H2A/H2B displacement (Ballare et al., 2013). Depletion or inhibition of MSK1 compromises hormonal gene regulation and blocks proliferation of breast cancer cells in vitro and in mouse xenografts (Reyes et al., 2013).
  • Signalling by progesterone to chromatin via kinase cascades
    J. Font Mateu, M. Wierer, R. Wright
    We discovered a non-mitotic role of PLK1 in the response of breast cancer cells to oestrogens and progesterone, acting as co-activator of their respective receptors (Wierer et al., 2013). We are completing these studies with an analysis of changes in the whole cell phosphoproteome, different times after hormone treatment. The goal is to integrate these results in a dynamic network (collaboration with J. Saez-Rodriguez, EBI, UK), which should help identifying relevant nodes connecting various signalling pathways to regulation of different gene cohorts.

Figure 1 Figure 1. Model for repression of genes that will be activated by hormone.

Selected Publications

  1. Ballaré C, Castellano G, Gaveglia L, Althammer S, González-Vallinas J, Eyras E, Le Dily, Zaurin R, Soronellas D, Vicent GP, Beato M.
    “Nucleosome driven transcription factor binding and gene regulation.”
    Mol Cell, 49:67-79 (2013).
  2. Reyes D, Ballare C, Castellano G, Soronellas D, Bago JR, Blanco J, Beato M.
    “Activation of Mitogen- and Stress-activated Kinase 1 is required for proliferation of breast cancer cells in response to estrogens and progesterone.”
    Oncogene, 2013 Apr 22. doi: 10.1038/onc.2013.95. [Epub ahead of print]
  3. Bertucci, PA, Nacht AS, Alló M, Rocha-Viegas L, Ballaré C, Castellano G, Zaurin R, Kornblihtt AR, Beato M, Vicent GP, Pecci A.
    “Progesterone Receptor induces bcl-x expression through intragenic binding sites favoring RNA Polymerase II elongation.”
    Nucleic Acids Res, 41:6072-86 (2013).
  4. Vicent GP, Nacht AS, Zaurin R, Reyes R, Soronellas D, Font-Mateu J, Beato M.
    “Unliganded receptor-mediated targeting of an RNA-containing repressive complex silences a subset of hormone inducible genes.”
    Genes Dev, 27:1179-1197 (2013).
  5. Wierer M, Verde G, Pisano P, Molina H, Font-Mateu J, Di Croce L, Beato M.
    “PLK1 signaling in breast cancer cells cooperates with estrogen receptor-dependent gene transcription.”
    Cell Reports, 3:1-12 (2013).
  6. Di Stefano B, Sardina JL, van Oevelen C, Kallin EM, Collombet S, Kalin EM, Vicent GP, Lu J, Thieffry D, Beato M, Graf T.
    “C/EBPα poises B cells for rapid reprogramming into induced pluripotent stem cells”
    Nature, doi: 10.1038/nature12885. Epub 2013 Dec 15.