Analysis of a Set of KDM5C Regulatory Genes Mutated in Neurodevelopmental Disorders Identifies Temporal Coexpression Brain Signatures
Dysregulation of transcriptional pathways is observed in multiple forms of neurodevelopmental disorders (NDDs), such as intellectual disability (ID), epilepsy and autism spectrum disorder (ASD). We previously demonstrated that the NDD genes encoding lysine-specific demethylase 5C (<i>KDM5C<...
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MDPI AG
2021-07-01
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| author | Loredana Poeta Agnese Padula Maria Brigida Lioi Hans van Bokhoven Maria Giuseppina Miano |
| author_facet | Loredana Poeta Agnese Padula Maria Brigida Lioi Hans van Bokhoven Maria Giuseppina Miano |
| author_sort | Loredana Poeta |
| collection | DOAJ |
| description | Dysregulation of transcriptional pathways is observed in multiple forms of neurodevelopmental disorders (NDDs), such as intellectual disability (ID), epilepsy and autism spectrum disorder (ASD). We previously demonstrated that the NDD genes encoding lysine-specific demethylase 5C (<i>KDM5C</i>) and its transcriptional regulators Aristaless related-homeobox (ARX), PHD Finger Protein 8 (PHF8) and Zinc Finger Protein 711 (<i>ZNF711</i>) are functionally connected. Here, we show their relation to each other with respect to the expression levels in human and mouse datasets and in vivo mouse analysis indicating that the coexpression of these syntenic X-chromosomal genes is temporally regulated in brain areas and cellular sub-types. In co-immunoprecipitation assays, we found that the homeotic transcription factor ARX interacts with the histone demethylase PHF8, indicating that this transcriptional axis is highly intersected. Furthermore, the functional impact of pathogenic mutations of <i>ARX</i>, <i>KDM5C</i>, <i>PHF8</i> and <i>ZNF711</i> was tested in lymphoblastoid cell lines (LCLs) derived from children with varying levels of syndromic ID establishing the direct correlation between defects in the KDM5C-H3K4me3 pathway and ID severity. These findings reveal novel insights into epigenetic processes underpinning NDD pathogenesis and provide new avenues for assessing developmental timing and critical windows for potential treatments. |
| first_indexed | 2024-03-10T09:38:15Z |
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| institution | Directory Open Access Journal |
| issn | 2073-4425 |
| language | English |
| last_indexed | 2024-03-10T09:38:15Z |
| publishDate | 2021-07-01 |
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| series | Genes |
| spelling | doaj.art-711cc1de183b4dff97296feb0d47cc4e2023-11-22T03:51:26ZengMDPI AGGenes2073-44252021-07-01127108810.3390/genes12071088Analysis of a Set of KDM5C Regulatory Genes Mutated in Neurodevelopmental Disorders Identifies Temporal Coexpression Brain SignaturesLoredana Poeta0Agnese Padula1Maria Brigida Lioi2Hans van Bokhoven3Maria Giuseppina Miano4Institute of Genetics and Biophysics Adriano Buzzati-Traverso, CNR, 80131 Naples, ItalyInstitute of Genetics and Biophysics Adriano Buzzati-Traverso, CNR, 80131 Naples, ItalyDepartment of Science, University of Basilicata, 85100 Potenza, ItalyDepartment of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboudumc, 6525 GA Nijmegen, The NetherlandsInstitute of Genetics and Biophysics Adriano Buzzati-Traverso, CNR, 80131 Naples, ItalyDysregulation of transcriptional pathways is observed in multiple forms of neurodevelopmental disorders (NDDs), such as intellectual disability (ID), epilepsy and autism spectrum disorder (ASD). We previously demonstrated that the NDD genes encoding lysine-specific demethylase 5C (<i>KDM5C</i>) and its transcriptional regulators Aristaless related-homeobox (ARX), PHD Finger Protein 8 (PHF8) and Zinc Finger Protein 711 (<i>ZNF711</i>) are functionally connected. Here, we show their relation to each other with respect to the expression levels in human and mouse datasets and in vivo mouse analysis indicating that the coexpression of these syntenic X-chromosomal genes is temporally regulated in brain areas and cellular sub-types. In co-immunoprecipitation assays, we found that the homeotic transcription factor ARX interacts with the histone demethylase PHF8, indicating that this transcriptional axis is highly intersected. Furthermore, the functional impact of pathogenic mutations of <i>ARX</i>, <i>KDM5C</i>, <i>PHF8</i> and <i>ZNF711</i> was tested in lymphoblastoid cell lines (LCLs) derived from children with varying levels of syndromic ID establishing the direct correlation between defects in the KDM5C-H3K4me3 pathway and ID severity. These findings reveal novel insights into epigenetic processes underpinning NDD pathogenesis and provide new avenues for assessing developmental timing and critical windows for potential treatments.https://www.mdpi.com/2073-4425/12/7/1088neurodevelopmental disordersX-chromosomeKDM5CH3K4me3disease mutationsNDD-related chromatinopathies |
| spellingShingle | Loredana Poeta Agnese Padula Maria Brigida Lioi Hans van Bokhoven Maria Giuseppina Miano Analysis of a Set of KDM5C Regulatory Genes Mutated in Neurodevelopmental Disorders Identifies Temporal Coexpression Brain Signatures Genes neurodevelopmental disorders X-chromosome KDM5C H3K4me3 disease mutations NDD-related chromatinopathies |
| title | Analysis of a Set of KDM5C Regulatory Genes Mutated in Neurodevelopmental Disorders Identifies Temporal Coexpression Brain Signatures |
| title_full | Analysis of a Set of KDM5C Regulatory Genes Mutated in Neurodevelopmental Disorders Identifies Temporal Coexpression Brain Signatures |
| title_fullStr | Analysis of a Set of KDM5C Regulatory Genes Mutated in Neurodevelopmental Disorders Identifies Temporal Coexpression Brain Signatures |
| title_full_unstemmed | Analysis of a Set of KDM5C Regulatory Genes Mutated in Neurodevelopmental Disorders Identifies Temporal Coexpression Brain Signatures |
| title_short | Analysis of a Set of KDM5C Regulatory Genes Mutated in Neurodevelopmental Disorders Identifies Temporal Coexpression Brain Signatures |
| title_sort | analysis of a set of kdm5c regulatory genes mutated in neurodevelopmental disorders identifies temporal coexpression brain signatures |
| topic | neurodevelopmental disorders X-chromosome KDM5C H3K4me3 disease mutations NDD-related chromatinopathies |
| url | https://www.mdpi.com/2073-4425/12/7/1088 |
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