Multiomic analysis implicates nuclear hormone receptor signalling in clustering epilepsy
Abstract Clustering Epilepsy (CE) is an epileptic disorder with neurological comorbidities caused by heterozygous variants of the X chromosome gene Protocadherin 19 (PCDH19). Recent studies have implicated dysregulation of the Nuclear Hormone Receptor (NHR) pathway in CE pathogenesis. To obtain a co...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2024-01-01
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| Series: | Translational Psychiatry |
| Online Access: | https://doi.org/10.1038/s41398-024-02783-5 |
| _version_ | 1797276250698416128 |
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| author | Rebekah de Nys Clare L. van Eyk Tarin Ritchie Rikke S. Møller Ingrid E. Scheffer Carla Marini Rudrarup Bhattacharjee Raman Kumar Jozef Gecz |
| author_facet | Rebekah de Nys Clare L. van Eyk Tarin Ritchie Rikke S. Møller Ingrid E. Scheffer Carla Marini Rudrarup Bhattacharjee Raman Kumar Jozef Gecz |
| author_sort | Rebekah de Nys |
| collection | DOAJ |
| description | Abstract Clustering Epilepsy (CE) is an epileptic disorder with neurological comorbidities caused by heterozygous variants of the X chromosome gene Protocadherin 19 (PCDH19). Recent studies have implicated dysregulation of the Nuclear Hormone Receptor (NHR) pathway in CE pathogenesis. To obtain a comprehensive overview of the impact and mechanisms of loss of PCDH19 function in CE pathogenesis, we have performed epigenomic, transcriptomic and proteomic analysis of CE relevant models. Our studies identified differential regulation and expression of Androgen Receptor (AR) and its targets in CE patient skin fibroblasts. Furthermore, our cell culture assays revealed the repression of PCDH19 expression mediated through ERα and the co-regulator FOXA1. We also identified a protein-protein interaction between PCDH19 and AR, expanding upon the intrinsic link between PCDH19 and the NHR pathway. Together, these results point to a novel mechanism of NHR signaling in the pathogenesis of CE that can be explored for potential therapeutic options. |
| first_indexed | 2024-03-07T15:25:37Z |
| format | Article |
| id | doaj.art-49c5d18714fc434c9a7aaf572909f7c5 |
| institution | Directory Open Access Journal |
| issn | 2158-3188 |
| language | English |
| last_indexed | 2024-03-07T15:25:37Z |
| publishDate | 2024-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Translational Psychiatry |
| spelling | doaj.art-49c5d18714fc434c9a7aaf572909f7c52024-03-05T17:06:33ZengNature Publishing GroupTranslational Psychiatry2158-31882024-01-011411910.1038/s41398-024-02783-5Multiomic analysis implicates nuclear hormone receptor signalling in clustering epilepsyRebekah de Nys0Clare L. van Eyk1Tarin Ritchie2Rikke S. Møller3Ingrid E. Scheffer4Carla Marini5Rudrarup Bhattacharjee6Raman Kumar7Jozef Gecz8Adelaide Medical School and Robinson Research Institute, The University of AdelaideAdelaide Medical School and Robinson Research Institute, The University of AdelaideAdelaide Medical School and Robinson Research Institute, The University of AdelaideDepartment of Epilepsy Genetics and Personalized Medicine (member of ERN EpiCARE), Danish Epilepsy CentreEpilepsy Research Centre, University of Melbourne, Austin HealthChild Neurology and Psychiatry Unit Children’s Hospital “G. Salesi” Azienda Ospedaliero-Universitaria delle Marche AnconaAdelaide Medical School and Robinson Research Institute, The University of AdelaideAdelaide Medical School and Robinson Research Institute, The University of AdelaideAdelaide Medical School and Robinson Research Institute, The University of AdelaideAbstract Clustering Epilepsy (CE) is an epileptic disorder with neurological comorbidities caused by heterozygous variants of the X chromosome gene Protocadherin 19 (PCDH19). Recent studies have implicated dysregulation of the Nuclear Hormone Receptor (NHR) pathway in CE pathogenesis. To obtain a comprehensive overview of the impact and mechanisms of loss of PCDH19 function in CE pathogenesis, we have performed epigenomic, transcriptomic and proteomic analysis of CE relevant models. Our studies identified differential regulation and expression of Androgen Receptor (AR) and its targets in CE patient skin fibroblasts. Furthermore, our cell culture assays revealed the repression of PCDH19 expression mediated through ERα and the co-regulator FOXA1. We also identified a protein-protein interaction between PCDH19 and AR, expanding upon the intrinsic link between PCDH19 and the NHR pathway. Together, these results point to a novel mechanism of NHR signaling in the pathogenesis of CE that can be explored for potential therapeutic options.https://doi.org/10.1038/s41398-024-02783-5 |
| spellingShingle | Rebekah de Nys Clare L. van Eyk Tarin Ritchie Rikke S. Møller Ingrid E. Scheffer Carla Marini Rudrarup Bhattacharjee Raman Kumar Jozef Gecz Multiomic analysis implicates nuclear hormone receptor signalling in clustering epilepsy Translational Psychiatry |
| title | Multiomic analysis implicates nuclear hormone receptor signalling in clustering epilepsy |
| title_full | Multiomic analysis implicates nuclear hormone receptor signalling in clustering epilepsy |
| title_fullStr | Multiomic analysis implicates nuclear hormone receptor signalling in clustering epilepsy |
| title_full_unstemmed | Multiomic analysis implicates nuclear hormone receptor signalling in clustering epilepsy |
| title_short | Multiomic analysis implicates nuclear hormone receptor signalling in clustering epilepsy |
| title_sort | multiomic analysis implicates nuclear hormone receptor signalling in clustering epilepsy |
| url | https://doi.org/10.1038/s41398-024-02783-5 |
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