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Deficiency of autism risk factor ASH1L in prefrontal cortex induces epigenetic aberrations and seizures
ASH1L, a histone methyltransferase, is identified as a top-ranking risk factor for autism spectrum disorder (ASD), however, little is known about the biological mechanisms underlying the link of ASH1L haploinsufficiency to ASD. Here we show that ASH1L expression and H3K4me3 level are significantly d...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8593046/ https://www.ncbi.nlm.nih.gov/pubmed/34782621 http://dx.doi.org/10.1038/s41467-021-26972-8 |
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author | Qin, Luye Williams, Jamal B. Tan, Tao Liu, Tiaotiao Cao, Qing Ma, Kaijie Yan, Zhen |
author_facet | Qin, Luye Williams, Jamal B. Tan, Tao Liu, Tiaotiao Cao, Qing Ma, Kaijie Yan, Zhen |
author_sort | Qin, Luye |
collection | PubMed |
description | ASH1L, a histone methyltransferase, is identified as a top-ranking risk factor for autism spectrum disorder (ASD), however, little is known about the biological mechanisms underlying the link of ASH1L haploinsufficiency to ASD. Here we show that ASH1L expression and H3K4me3 level are significantly decreased in the prefrontal cortex (PFC) of postmortem tissues from ASD patients. Knockdown of Ash1L in PFC of juvenile mice induces the downregulation of risk genes associated with ASD, intellectual disability (ID) and epilepsy. These downregulated genes are enriched in excitatory and inhibitory synaptic function and have decreased H3K4me3 occupancy at their promoters. Furthermore, Ash1L deficiency in PFC causes the diminished GABAergic inhibition, enhanced glutamatergic transmission, and elevated PFC pyramidal neuronal excitability, which is associated with severe seizures and early mortality. Chemogenetic inhibition of PFC pyramidal neuronal activity, combined with the administration of GABA enhancer diazepam, rescues PFC synaptic imbalance and seizures, but not autistic social deficits or anxiety-like behaviors. These results have revealed the critical role of ASH1L in regulating synaptic gene expression and seizures, which provides insights into treatment strategies for ASH1L-associated brain diseases. |
format | Online Article Text |
id | pubmed-8593046 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-85930462021-11-19 Deficiency of autism risk factor ASH1L in prefrontal cortex induces epigenetic aberrations and seizures Qin, Luye Williams, Jamal B. Tan, Tao Liu, Tiaotiao Cao, Qing Ma, Kaijie Yan, Zhen Nat Commun Article ASH1L, a histone methyltransferase, is identified as a top-ranking risk factor for autism spectrum disorder (ASD), however, little is known about the biological mechanisms underlying the link of ASH1L haploinsufficiency to ASD. Here we show that ASH1L expression and H3K4me3 level are significantly decreased in the prefrontal cortex (PFC) of postmortem tissues from ASD patients. Knockdown of Ash1L in PFC of juvenile mice induces the downregulation of risk genes associated with ASD, intellectual disability (ID) and epilepsy. These downregulated genes are enriched in excitatory and inhibitory synaptic function and have decreased H3K4me3 occupancy at their promoters. Furthermore, Ash1L deficiency in PFC causes the diminished GABAergic inhibition, enhanced glutamatergic transmission, and elevated PFC pyramidal neuronal excitability, which is associated with severe seizures and early mortality. Chemogenetic inhibition of PFC pyramidal neuronal activity, combined with the administration of GABA enhancer diazepam, rescues PFC synaptic imbalance and seizures, but not autistic social deficits or anxiety-like behaviors. These results have revealed the critical role of ASH1L in regulating synaptic gene expression and seizures, which provides insights into treatment strategies for ASH1L-associated brain diseases. Nature Publishing Group UK 2021-11-15 /pmc/articles/PMC8593046/ /pubmed/34782621 http://dx.doi.org/10.1038/s41467-021-26972-8 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Qin, Luye Williams, Jamal B. Tan, Tao Liu, Tiaotiao Cao, Qing Ma, Kaijie Yan, Zhen Deficiency of autism risk factor ASH1L in prefrontal cortex induces epigenetic aberrations and seizures |
title | Deficiency of autism risk factor ASH1L in prefrontal cortex induces epigenetic aberrations and seizures |
title_full | Deficiency of autism risk factor ASH1L in prefrontal cortex induces epigenetic aberrations and seizures |
title_fullStr | Deficiency of autism risk factor ASH1L in prefrontal cortex induces epigenetic aberrations and seizures |
title_full_unstemmed | Deficiency of autism risk factor ASH1L in prefrontal cortex induces epigenetic aberrations and seizures |
title_short | Deficiency of autism risk factor ASH1L in prefrontal cortex induces epigenetic aberrations and seizures |
title_sort | deficiency of autism risk factor ash1l in prefrontal cortex induces epigenetic aberrations and seizures |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8593046/ https://www.ncbi.nlm.nih.gov/pubmed/34782621 http://dx.doi.org/10.1038/s41467-021-26972-8 |
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