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Generation of inducible SMARCAL1 knock-down iPSC to model severe Schimke immune-osseous dysplasia reveals a link between replication stress and altered expression of master differentiation genes

Giusj Monia Pugliese, Federico Salaris, Valentina Palermo, Veronica Marabitti, Nicolò Morina, Alessandro Rosa, Annapaola Franchitto, Pietro Pichierri
doi: https://doi.org/10.1101/546093
Giusj Monia Pugliese
1Mechanisms, Biomarkers and Models Unit, Department of Environment and Health, Istituto Superiore di Sanità - Viale Regina Elena 299, 00161 Rome (Italy)
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Federico Salaris
2Center for Life Nano Science, Istituto Italiano di Tecnologia, Viale Regina Elena 291, 00161 Rome (Italy)
3Department of Biology and Biotechnology Charles Darwin, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome (Italy)
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Valentina Palermo
1Mechanisms, Biomarkers and Models Unit, Department of Environment and Health, Istituto Superiore di Sanità - Viale Regina Elena 299, 00161 Rome (Italy)
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Veronica Marabitti
1Mechanisms, Biomarkers and Models Unit, Department of Environment and Health, Istituto Superiore di Sanità - Viale Regina Elena 299, 00161 Rome (Italy)
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Nicolò Morina
1Mechanisms, Biomarkers and Models Unit, Department of Environment and Health, Istituto Superiore di Sanità - Viale Regina Elena 299, 00161 Rome (Italy)
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Alessandro Rosa
2Center for Life Nano Science, Istituto Italiano di Tecnologia, Viale Regina Elena 291, 00161 Rome (Italy)
3Department of Biology and Biotechnology Charles Darwin, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome (Italy)
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Annapaola Franchitto
1Mechanisms, Biomarkers and Models Unit, Department of Environment and Health, Istituto Superiore di Sanità - Viale Regina Elena 299, 00161 Rome (Italy)
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Pietro Pichierri
1Mechanisms, Biomarkers and Models Unit, Department of Environment and Health, Istituto Superiore di Sanità - Viale Regina Elena 299, 00161 Rome (Italy)
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  • For correspondence: pietro.pichierri@iss.it
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ABSTRACT

The Schimke immuno-osseous dysplasia is an autosomal recessive genetic osteochondrodysplasia characterized by dysmorphism, spondyloepiphyseal dysplasia, nephrotic syndrome and frequently T cell immunodeficiency. Several hypotheses have been proposed to explain pathophysiology of the disease, however, the mechanism by which SMARCAL1 mutations cause the syndrome is elusive. Indeed, animal models of the disease are absent or useless to provide insight into the disease mechanism, since they do not recapitulate the phenotype. We generated a conditional knockdown model of SMARCAL1 in iPSCs to mimic conditions of cells with severe form the disease. Here, we characterize this model for the presence of phenotype linked to the replication caretaker role of SMARCAL1 using multiple cellular endpoints. Our data show that conditional knockdown of SMARCAL1 in human iPSCs induces replication-dependent and chronic accumulation of DNA damage triggering the DNA damage response. Furthermore, they indicate that accumulation of DNA damage and activation of the DNA damage response correlates with increased levels of R-loops and replication-transcription interference. Finally, we provide data showing that, in SMARCAL1-deficient iPSCs, DNA damage response can be maintained active also after differentiation, possibly contributing to the observed altered expression of a subset of germ layer-specific master genes. In conclusion, our conditional SMARCAL1 iPSCs may represent a powerful model where studying pathogenetic mechanisms of severe Schimke immuno-osseous dysplasia, thus overcoming the reported inability of different model systems to recapitulate the disease.

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Posted February 10, 2019.
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Generation of inducible SMARCAL1 knock-down iPSC to model severe Schimke immune-osseous dysplasia reveals a link between replication stress and altered expression of master differentiation genes
Giusj Monia Pugliese, Federico Salaris, Valentina Palermo, Veronica Marabitti, Nicolò Morina, Alessandro Rosa, Annapaola Franchitto, Pietro Pichierri
bioRxiv 546093; doi: https://doi.org/10.1101/546093
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Generation of inducible SMARCAL1 knock-down iPSC to model severe Schimke immune-osseous dysplasia reveals a link between replication stress and altered expression of master differentiation genes
Giusj Monia Pugliese, Federico Salaris, Valentina Palermo, Veronica Marabitti, Nicolò Morina, Alessandro Rosa, Annapaola Franchitto, Pietro Pichierri
bioRxiv 546093; doi: https://doi.org/10.1101/546093

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