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
  • 2023-06
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • 2024-04
  • 2024-05

    • miR a has been extensively studied in different

    2018-11-09

    miR-29a has been extensively studied in different fields. miR-29a has been reported to be associated with cardiac hypertrophy and fibrosis (Roncarati et al., 2014), and functions as a negative regulator of extracellular matrix remodeling (van Rooij et al., 2008). We have previously reported that miR-29a can also act as an important regulator of the inflammatory response (Chen et al., 2011). In the current study, using miRNA gain/loss-of-function analyses and a well-established in vitro VSMC differentiation model, we confirmed a regulatory role for miR-29a in VSMC differentiation from ESCs. An important role of miR-29a in VSMC differentiation has been further confirmed in our well-established in vivo VSMC differentiation model with Matrigel™ implantation. One of the new findings in the current study is that we have identified YY1 as the target gene of miR-29a during VSMC differentiation from ESCs. YY1 (also known as Yin Yang1, NF-E1, UCRBP and CF1), a ubiquitous and dual-function GLI-Kruppel zinc finger transcription factor, was first identified on the basis of its capacity to negatively regulate the adeno-associated virus P5 promoter (Shi et al., 1991). Recent studies have suggested that YY1 functions as a transcription co-factor independent of its DNA binding activity (Deng et al., 2010). It has been reported that YY1 is an important inhibitor of muscle cell differentiation and expression of muscle-specific genes (Ellis et al., 2002). Another study has reported that VSMC phenotype is also regulated by the YY1 (Favot et al., 2005), yet the potential interplay between YY1 and VSMC biology is still unclear and needs further investigation (Aikawa, 2007). In the current study, we have observed that YY1 is negatively regulated by miR-29a, and re-activation of YY1 impairs VSMC gene activation induced by miR-29a over-expression, supporting an important role of YY1 in miR-29a-mediated VSMC differentiation from ESCs.
    Conclusion In the current study, we reported a novel function of miR-29a in VSMC differentiation from stem ck1 inhibitor in vitro and in vivo, and provided comprehensive evidence to support that YY1 is a genuine mRNA target of miR-29a during VSMC differentiation. Moreover, our data suggest that YY1 is a negative regulator of VSMC related transcription factors (SRF, Myocd, and MEF-2C), and repression of YY1 by miR-29a is the underlying mechanism of miR-29a-mediated VSMC differentiation from ESCs (Fig. 7).
    Conflict of interest disclosure
    Author contributions
    Introduction Ataxia-Telangiectasia (A-T; OMIM208900) is an autosomal recessive syndrome caused by compound heterozygous null mutations in the locus encoding the ATM kinase at chromosome 11q22 (Savitsky et al., 1995) (“classical” A-T). Most A-T patients suffer from severe cerebellar degeneration due to Purkinje cell death, B and T cell immunodeficiency and increased cancer predisposition (Boder and Sedgwick, 1958; Lavin, 2008; McKinnon, 2012; Shiloh, 2003). Moreover, haploinsufficiency for ATM, estimated to occur in 1.5-2% of the population worldwide (Swift et al., 1986), increases the risk of cancer and heart disease and decreases lifespan (Su and Swift, 2000; Swift and Chase, 1983). However, how alterations in ATM copy number result in such pleiotropic phenotypes remains incompletely understood. Nucleoplasmic ATM is activated in response to DNA double-strand breaks (DSB) to orchestrate the cellular DNA Damage Response (DDR) and promote cell cycle checkpoint activation and DSB repair (Paull, 2015; Shiloh and Ziv, 2013). In ATM-deficient developing lymphocytes, broken DNA ends at “programmed” DSBs remain unrepaired or are repaired aberrantly, leading to T and B cell immunodeficiency and oncogenic translocations, respectively (Callen et al., 2007; Franco et al., 2006). In contrast, the contribution of defective DSB repair to the neurodegenerative phenotypes observed in A-T is less well understood. In this context, the finding that ATM may localize primarily to the cytoplasm in post-mitotic neurons (Barlow et al., 2000; Oka and Takashima, 1998), together with its emerging cytoplasmic functions in the regulation of oxidative stress and metabolism (Ambrose and Gatti, 2013; Paull, 2015; Valentin-Vega et al., 2012; Zhang et al., 2015), may suggest a mechanism independent of DSB repair (Carlessi et al., 2013). However, Atm−/− mice (Lavin, 2013) and ATM−/− pigs (Beraldi et al., 2015) do not manifest ataxia or significant cerebellar pathology, underscoring the need for novel human cell-based approaches to model neurodegeneration.