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While the underlying molecular changes caused by mTOR activation in TSC have previously been investigated, the drivers of these transcriptional change have not been fully elucidated. A better understanding of the perturbed transcriptional regulation could lead to the identification of novel pathways for therapeutic intervention not only in TSC, but other genetic epilepsies in which mTOR activation plays a key role, such as focal cortical dysplasia 2b (FCD). Here, we analyzed RNA sequencing data from cortical tubers and a tsc2<jats:sup>\u2212\/\u2212<\/jats:sup>zebrafish. We identified differential expression of the transcription factors (TFs) SPI1\/PU.1, IRF8, GBX2, and IKZF1 of which SPI1\/PU.1 and IRF8 targets were enriched among the differentially expressed genes. Furthermore, for SPI1\/PU.1 these findings were conserved in TSC zebrafish model. Next, we confirmed overexpression of SPI1\/PU.1 on the RNA and protein level in a separate cohort of surgically resected TSC tubers and FCD tissue, in fetal TSC tissue, and a<jats:italic>Tsc1<\/jats:italic><jats:sup>GFAP\u2212\/\u2212<\/jats:sup>mouse model of TSC. Subsequently, we validated the expression of SPI1\/PU.1 in dysmorphic cells with mTOR activation in TSC tubers. In fetal TSC, we detected SPI1\/PU.1 expression prenatally and elevated RNA Spi1 expression in<jats:italic>Tsc1<\/jats:italic><jats:sup>GFAP\u2212\/\u2212<\/jats:sup>mice before the development of seizures. Finally,<jats:italic>in vitro<\/jats:italic>, we identified that in astrocytes and neurons<jats:italic>SPI1<\/jats:italic>transcription was driven by H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub>\u2010induced oxidative stress, independent of mTOR. We identified SPI1\/PU.1 as a novel TF involved in the pro\u2010inflammatory gene expression of malformed cells in TSC and FCD 2b. This transcriptional program is activated in response to oxidative stress and already present prenatally. Importantly, SPI1\/PU.1 protein appears to be strictly limited to malformed cells, as we did not find SPI1\/PU.1 protein expression in mice nor in our<jats:italic>in vitro<\/jats:italic>models.<\/jats:p>","DOI":"10.1111\/bpa.12949","type":"journal-article","created":{"date-parts":[[2021,3,31]],"date-time":"2021-03-31T06:02:15Z","timestamp":1617170535000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Upregulation of the pathogenic transcription factor SPI1\/PU.1 in tuberous sclerosis complex and focal cortical dysplasia by oxidative stress"],"prefix":"10.1111","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6869-3697","authenticated-orcid":false,"given":"Till S.","family":"Zimmer","sequence":"first","affiliation":[{"name":"Department of (Neuro)Pathology Amsterdam Neuroscience Amsterdam UMC University of Amsterdam Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8313-6282","authenticated-orcid":false,"given":"Anatoly","family":"Korotkov","sequence":"additional","affiliation":[{"name":"Department of (Neuro)Pathology Amsterdam Neuroscience Amsterdam UMC University of Amsterdam Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan","family":"Zwakenberg","sequence":"additional","affiliation":[{"name":"Center for Molecular Medicine Molecular Cancer Research University Medical Center Utrecht Utrecht the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Floor E.","family":"Jansen","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurology, Brain Center University Medical Center Utrecht Utrecht the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fried J. T.","family":"Zwartkruis","sequence":"additional","affiliation":[{"name":"Center for Molecular Medicine Molecular Cancer Research University Medical Center Utrecht Utrecht the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas R.","family":"Rensing","sequence":"additional","affiliation":[{"name":"Department of Neurology Washington University Saint Louis MO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Wong","sequence":"additional","affiliation":[{"name":"Department of Neurology Washington University Saint Louis MO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9102-7353","authenticated-orcid":false,"given":"Angelika","family":"M\u00fchlebner","sequence":"additional","affiliation":[{"name":"Department of (Neuro)Pathology Amsterdam Neuroscience Amsterdam UMC University of Amsterdam Amsterdam the Netherlands"},{"name":"Department of Pathology University Medical Center Utrecht Utrecht the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5747-3202","authenticated-orcid":false,"given":"Erwin A.","family":"van Vliet","sequence":"additional","affiliation":[{"name":"Department of (Neuro)Pathology Amsterdam Neuroscience Amsterdam UMC University of Amsterdam Amsterdam the Netherlands"},{"name":"Center for Neuroscience Swammerdam Institute for Life Sciences University of Amsterdam Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleonora","family":"Aronica","sequence":"additional","affiliation":[{"name":"Department of (Neuro)Pathology Amsterdam Neuroscience Amsterdam UMC University of Amsterdam Amsterdam the Netherlands"},{"name":"Stichting Epilepsie Instellingen Nederland (SEIN) Heemstede the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James 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