Coding and small non-coding transcriptional landscape of tuberous sclerosis complex cortical tubers: implications for pathophysiology and treatment
Abstract Tuberous Sclerosis Complex (TSC) is a rare genetic disorder that results from a mutation in the TSC1 or TSC2 genes leading to constitutive activation of the mechanistic target of rapamycin complex 1 (mTORC1). TSC is associated with autism, intellectual disability and severe epilepsy. Cortic...
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2017
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oai:doaj.org-article:201057c7a40346ccbc3ef966170890fc2021-12-02T15:06:18ZCoding and small non-coding transcriptional landscape of tuberous sclerosis complex cortical tubers: implications for pathophysiology and treatment10.1038/s41598-017-06145-82045-2322https://doaj.org/article/201057c7a40346ccbc3ef966170890fc2017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-06145-8https://doaj.org/toc/2045-2322Abstract Tuberous Sclerosis Complex (TSC) is a rare genetic disorder that results from a mutation in the TSC1 or TSC2 genes leading to constitutive activation of the mechanistic target of rapamycin complex 1 (mTORC1). TSC is associated with autism, intellectual disability and severe epilepsy. Cortical tubers are believed to represent the neuropathological substrates of these disabling manifestations in TSC. In the presented study we used high-throughput RNA sequencing in combination with systems-based computational approaches to investigate the complexity of the TSC molecular network. Overall we detected 438 differentially expressed genes and 991 differentially expressed small non-coding RNAs in cortical tubers compared to autopsy control brain tissue. We observed increased expression of genes associated with inflammatory, innate and adaptive immune responses. In contrast, we observed a down-regulation of genes associated with neurogenesis and glutamate receptor signaling. MicroRNAs represented the largest class of over-expressed small non-coding RNA species in tubers. In particular, our analysis revealed that the miR-34 family (including miR-34a, miR-34b and miR-34c) was significantly over-expressed. Functional studies demonstrated the ability of miR-34b to modulate neurite outgrowth in mouse primary hippocampal neuronal cultures. This study provides new insights into the TSC transcriptomic network along with the identification of potential new treatment targets.James D. MillsAnand M. IyerJackelien van ScheppingenAnika BongaartsJasper J. AninkBart JanssenTill S. ZimmerWim G. SplietPeter C. van RijenFloor E. JansenMartha FeuchtJohannes A. HainfellnerPavel KrsekJosef ZamecnikKatarzyna KotulskaSergiusz JozwiakAnna JansenLieven LagaePaolo CuratoloDavid J. KwiatkowskiR. Jeroen PasterkampKetharini SenthilkumarLars von OerthelMarco F. HoekmanJan A. GorterPeter B. CrinoAngelika MühlebnerBrendon P. SciclunaEleonora AronicaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-16 (2017) |
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DOAJ |
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DOAJ |
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EN |
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Medicine R Science Q |
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Medicine R Science Q James D. Mills Anand M. Iyer Jackelien van Scheppingen Anika Bongaarts Jasper J. Anink Bart Janssen Till S. Zimmer Wim G. Spliet Peter C. van Rijen Floor E. Jansen Martha Feucht Johannes A. Hainfellner Pavel Krsek Josef Zamecnik Katarzyna Kotulska Sergiusz Jozwiak Anna Jansen Lieven Lagae Paolo Curatolo David J. Kwiatkowski R. Jeroen Pasterkamp Ketharini Senthilkumar Lars von Oerthel Marco F. Hoekman Jan A. Gorter Peter B. Crino Angelika Mühlebner Brendon P. Scicluna Eleonora Aronica Coding and small non-coding transcriptional landscape of tuberous sclerosis complex cortical tubers: implications for pathophysiology and treatment |
| description |
Abstract Tuberous Sclerosis Complex (TSC) is a rare genetic disorder that results from a mutation in the TSC1 or TSC2 genes leading to constitutive activation of the mechanistic target of rapamycin complex 1 (mTORC1). TSC is associated with autism, intellectual disability and severe epilepsy. Cortical tubers are believed to represent the neuropathological substrates of these disabling manifestations in TSC. In the presented study we used high-throughput RNA sequencing in combination with systems-based computational approaches to investigate the complexity of the TSC molecular network. Overall we detected 438 differentially expressed genes and 991 differentially expressed small non-coding RNAs in cortical tubers compared to autopsy control brain tissue. We observed increased expression of genes associated with inflammatory, innate and adaptive immune responses. In contrast, we observed a down-regulation of genes associated with neurogenesis and glutamate receptor signaling. MicroRNAs represented the largest class of over-expressed small non-coding RNA species in tubers. In particular, our analysis revealed that the miR-34 family (including miR-34a, miR-34b and miR-34c) was significantly over-expressed. Functional studies demonstrated the ability of miR-34b to modulate neurite outgrowth in mouse primary hippocampal neuronal cultures. This study provides new insights into the TSC transcriptomic network along with the identification of potential new treatment targets. |
| format |
article |
| author |
James D. Mills Anand M. Iyer Jackelien van Scheppingen Anika Bongaarts Jasper J. Anink Bart Janssen Till S. Zimmer Wim G. Spliet Peter C. van Rijen Floor E. Jansen Martha Feucht Johannes A. Hainfellner Pavel Krsek Josef Zamecnik Katarzyna Kotulska Sergiusz Jozwiak Anna Jansen Lieven Lagae Paolo Curatolo David J. Kwiatkowski R. Jeroen Pasterkamp Ketharini Senthilkumar Lars von Oerthel Marco F. Hoekman Jan A. Gorter Peter B. Crino Angelika Mühlebner Brendon P. Scicluna Eleonora Aronica |
| author_facet |
James D. Mills Anand M. Iyer Jackelien van Scheppingen Anika Bongaarts Jasper J. Anink Bart Janssen Till S. Zimmer Wim G. Spliet Peter C. van Rijen Floor E. Jansen Martha Feucht Johannes A. Hainfellner Pavel Krsek Josef Zamecnik Katarzyna Kotulska Sergiusz Jozwiak Anna Jansen Lieven Lagae Paolo Curatolo David J. Kwiatkowski R. Jeroen Pasterkamp Ketharini Senthilkumar Lars von Oerthel Marco F. Hoekman Jan A. Gorter Peter B. Crino Angelika Mühlebner Brendon P. Scicluna Eleonora Aronica |
| author_sort |
James D. Mills |
| title |
Coding and small non-coding transcriptional landscape of tuberous sclerosis complex cortical tubers: implications for pathophysiology and treatment |
| title_short |
Coding and small non-coding transcriptional landscape of tuberous sclerosis complex cortical tubers: implications for pathophysiology and treatment |
| title_full |
Coding and small non-coding transcriptional landscape of tuberous sclerosis complex cortical tubers: implications for pathophysiology and treatment |
| title_fullStr |
Coding and small non-coding transcriptional landscape of tuberous sclerosis complex cortical tubers: implications for pathophysiology and treatment |
| title_full_unstemmed |
Coding and small non-coding transcriptional landscape of tuberous sclerosis complex cortical tubers: implications for pathophysiology and treatment |
| title_sort |
coding and small non-coding transcriptional landscape of tuberous sclerosis complex cortical tubers: implications for pathophysiology and treatment |
| publisher |
Nature Portfolio |
| publishDate |
2017 |
| url |
https://doaj.org/article/201057c7a40346ccbc3ef966170890fc |
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