ArticleHuman molecular genetics2019
Histone demethylase KDM5C is a SAHA-sensitive central hub at the crossroads of transcriptional axes involved in multiple neurodevelopmental disorders.
Article in Human molecular genetics, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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25 citing papers in PubMed, 27 citations in OpenAlex.
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- Expanding the phenotypic Spectrum of ZNF711: Autism and epilepsy in two siblings.Epilepsy & behavior reports · 2026Article
- Identification of Novel Co-OccurringThe application of clinical genetics · 2026Article
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- Evolutionary sex bias in cognitive response to new environmental risk factor - PM2.5.Biology of sex differences · 2025Review
- Cannabidiol attenuates epileptic phenotype and increases survival in a mouse model of developmental and epileptic encephalopathy type 1.Epilepsia · 2025Article
- The Aggravation of Neuropsychiatric Symptoms in the Offspring of a Korean Family with Intellectual Disability and Developmental Delay Caused by a NovelInternational journal of molecular sciences · 2024Article
- Formerly degenerate seventh zinc finger domain from transcription factor ZNF711 rehabilitated by experimental NMR structure.Protein science : a publication of the Protein Society · 2024Article
- Formerly degenerate seventh zinc finger domain from transcription factor ZNF711 rehabilitated by experimental NMR structure.bioRxiv : the preprint server for biology · 2024Article
- Suberoylanilide Hydroxamic Acid (SAHA) Is a Driver Molecule of Neuroplasticity: Implication for Neurological Diseases.Biomolecules · 2023Review
- Expanding the genetics and phenotypic spectrum of Lysine-specific demethylase 5C (KDM5C): a report of 13 novel variants.European journal of human genetics : EJHG · 2023Article
- PGCLCs of human 45,XO reveal pathogenetic pathways of neurocognitive and psychosocial disorders.Cell & bioscience · 2022Article
- The Chromatin-Oxygen Sensor GeneInternational journal of molecular sciences · 2022Article
- Deregulation of microtubule organization and RNA metabolism in Arx models for lissencephaly and developmental epileptic encephalopathy.Human molecular genetics · 2022Article
- Further Delineation of Duplications ofInternational journal of molecular sciences · 2022Review
- Reprogramming of the epigenome in neurodevelopmental disorders.Critical reviews in biochemistry and molecular biology · 2022Review
- Astroglia in Autism Spectrum Disorder.International journal of molecular sciences · 2021Review
- X-factors in human disease: impact of gene content and dosage regulation.Human molecular genetics · 2021Review
- Article
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Authors and funding
18 authors at 12 institutions in 6 countries.
Funding
Abstract
A disproportional large number of neurodevelopmental disorders (NDDs) is caused by variants in genes encoding transcription factors and chromatin modifiers. However, the functional interactions between the corresponding proteins are only partly known. Here, we show that KDM5C, encoding a H3K4 demethylase, is at the intersection of transcriptional axes under the control of three regulatory proteins ARX, ZNF711 and PHF8. Interestingly, mutations in all four genes (KDM5C, ARX, ZNF711 and PHF8) are associated with X-linked NDDs comprising intellectual disability as a core feature. in vitro analysis of the KDM5C promoter revealed that ARX and ZNF711 function as antagonist transcription factors that activate KDM5C expression and compete for the recruitment of PHF8. Functional analysis of mutations in these genes showed a correlation between phenotype severity and the reduction in KDM5C transcriptional activity. The KDM5C decrease was associated with a lack of repression of downstream target genes Scn2a, Syn1 and Bdnf in the embryonic brain of Arx-null mice. Aiming to correct the faulty expression of KDM5C, we studied the effect of the FDA-approved histone deacetylase inhibitor suberanilohydroxamic acid (SAHA). In Arx-KO murine ES-derived neurons, SAHA was able to rescue KDM5C depletion, recover H3K4me3 signalling and improve neuronal differentiation. Indeed, in ARX/alr-1-deficient Caenorhabditis elegans animals, SAHA was shown to counteract the defective KDM5C/rbr-2-H3K4me3 signalling, recover abnormal behavioural phenotype and ameliorate neuronal maturation. Overall, our studies indicate that KDM5C is a conserved and druggable effector molecule across a number of NDDs for whom the use of SAHA may be considered a potential therapeutic strategy.
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