Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-07
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • 2024-04

    • In conclusion the MC approach described

    2018-10-24

    In conclusion, the MC approach described in this study provides a platform to generate a population of human PAX7+ myogenic progenitors from PS GSK2656157 that can be terminally differentiated into MHC+ myocytes in vitro that is equivalent to iPAX7 cells. However, further development of the methodology will be necessary to significantly increase the in vivo regenerative potential before it could be considered as an alternative to the LV expression system for translational therapeutic applications.
    Authorship contributions
    Competing financial interests
    Acknowledgements This project was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health under Award Number R01 AR055299, the Parent Project Muscular Dystrophy (PPMD) (#00613), ADVault Inc., and MyDirectives.com (R.C.R.P.). The monoclonal antibody to MHC was obtained from the Developmental Studies Hybridoma Bank developed under the auspices of the NICHD and maintained by the University of Iowa. We thank Cynthia Dekay for assistance in graphic design.
    Introduction The pluripotent stem cell state is maintained by a core set of transcription factors (e.g., Oct4, Sox2, and Nanog) that activate self-renewal genes and suppress lineage-specific differentiation pathways (Dejosez and Zwaka, 2012; Ng and Surani, 2011). Although pluripotency-related transcription factors are known to bind upstream of several DNA repair genes (Marson et al., 2008), the exact links that connect genomic integrity, DNA repair, and pluripotency have not yet been clearly defined. A second class of transcription factors helps maintain pluripotency by controlling general cell-vital programs that are critical for the rapid growth of pluripotent stem cells (Smith et al., 2011; Dejosez et al., 2010; Dejosez and Zwaka, 2012). Ronin (Thap11) belongs to this second class and is hence a suitable candidate for altering the DNA repair capacity of pluripotent stem cells. Ronin is a DNA-binding protein that is essential for pluripotent stem cells and is known to regulate various genes that are important for the cellular homeostasis of highly prolific cells (Dejosez et al., 2010, 2008). Here, we provide evidence that Ronin also influences the DNA repair machinery of embryonic stem cells (ESCs). We show that Ronin regulates genes involved in the response to UV-C irradiation, and that conditional Ronin knockout increases the sensitivity of ESCs to DNA damage and activates the Atr-mediated DNA damage response. Our findings suggest that, along with lineage-specific transcription factors like Oct4 and Sox2, Ronin helps to maintain the uniquely robust genomic integrity of pluripotent stem cells.
    Materials and methods
    Results
    Discussion We herein use Ronin-knockout ESCs to show that Ronin adjusts the cellular DNA damage response of pluripotent cells to the more stringent needs of the early embryo. We report evidence suggesting that Ronin may exert its effects on the DNA repair capacity by transcriptionally regulating DNA repair genes. The important role of Ronin during early embryogenesis and the lethal phenotype associated with its knockout fit this model (Dejosez et al., 2008). DNA maintenance and repair are costly in terms of their energy requirements, biomass needs, and the number of involved proteins, which must be provided in a manner appropriate to other stringent needs of the early embryo (Dejosez et al., 2010; Vander Heiden et al., 2009). Not all cells require their DNA integrity to be so robustly maintained. For example, non-cycling cells have relatively low needs for DNA repair, and DNA damage is not as consequential. On the other hand, highly prolific cells, such as those of the embryo, have rapid and abbreviated cell cycles that increase their sensitivity to blocked DNA replication (Bielas and Heddle, 2004; Harfouche and Martin, 2010; Mandal et al., 2011; McKinnon, 2009). This weakness reflects a finely tuned balance of DNA repair, cell cycle arrest, and apoptosis (Corbet et al., 1999; de Waard et al., 2008; Savatier et al., 2002; White and Dalton, 2005). The results of our present study suggest that Ronin is part of this fine-tuning system, as its loss is specifically associated with particular aspects of DNA damage sensitivity. Indeed, as Ronin is expressed in oocytes (Dejosez et al., 2008), our observation might extend to germ cells that have been shown to share the high levels of genomic integrity seen in ES cells (Murphey et al., 2013).