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The BRG1 ATPase of chromatin remodeling complexes is involved in modulation of mesenchymal stem cell senescence through RB–P53 pathways

Oncogene volume 29, pages 5452–5463 (2010)Cite this article

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Abstract

We focused our attention on brahma-related gene 1 (BRG1), the ATPase subunit of the SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeling complex, and analyzed its role in mesenchymal stem cell (MSC) biology. We hypothesized that deviation from the correct concentration of these proteins, which act at the highest level of gene regulation, may be deleterious for cells. We wanted to know what would happen if a cell had to cope with altered regulation of gene expression, either by upregulation or downregulation of BRG1. We assumed that cells would try to restore homeostasis or, alternatively, that the event could trigger senescence/apoptosis phenomena. To this end, in MSCs, we silenced BRG1gene. Knockdown of BRG1 expression induced a significant increase in senescent cells and decrease in apoptotic cells. It is interesting that BRG1 downregulation also induced an increase in heterochromatin. At the molecular level, these phenomena were associated with activation of retinoblastoma-like protein 2 (RB2)/P130- and P53-related pathways. Senescence was accompanied by reduced expression of some stemness-related genes. This is consistent with our previous research, which showed that BRG1 upregulation by ectopic expression also induced senescence processes. Together, these data suggest that BRG1 belongs to a class of genes whose expression is tightly regulated; hence, subtle alterations in BRG1 activity seem to negatively affect mechanisms regulating chromatin status and, in turn, impair cellular physiology.

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Acknowledgements

This work was partially supported by SHRO funds to UG and AG. We thank Maria Rosaria Cipollaro for technical assistance. We thank Dr Francesca Pentimalli for helpful discussion.

Author contributions: Tiziana Squillaro: conception and design, performed experiments; Nicola Alessio: conception and design, performed experiments; Marilena Cipollaro: assembly of data, data analysis and interpretation; Luigi Bagella: provision of study material, data analysis and interpretation and financial support; Antonio Giordano: conception and design, data analysis and interpretation and financial support; Umberto Galderisi: conception and design, data analysis and interpretation, paper writing and financial support.

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Authors and Affiliations

  1. Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, Temple University, Philadelphia, PA, USA

    N Alessio, T Squillaro, L Bagella, A Giordano & U Galderisi

  2. Department of Biomedical Sciences, Division of Biochemistry and Biophysics, University of Sassari, Sassari, Italy

    N Alessio & L Bagella

  3. Medical Genetics, University of Siena, Siena, Italy

    T Squillaro

  4. Department of Experimental Medicine, Biotechnology and Molecular Biology Section, Second University of Naples, Naples, Italy

    M Cipollaro & U Galderisi

  5. Human Pathology and Oncology Department, University of Siena, Siena, Italy

    A Giordano

  6. Human Health Foundation, Spoleto, Italy

    A Giordano

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Alessio, N., Squillaro, T., Cipollaro, M. et al. The BRG1 ATPase of chromatin remodeling complexes is involved in modulation of mesenchymal stem cell senescence through RB–P53 pathways. Oncogene 29, 5452–5463 (2010). https://doi.org/10.1038/onc.2010.285

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