Transcriptomic dysregulation and autistic-like behaviors in Kmt2c haploinsufficient mice rescued by an LSD1 inhibitor

  1. Nakamura, Takumi ORCID logo
  2. Yoshihara, Toru
  3. Tanegashima, Chiharu
  4. Kadota, Mitsutaka
  5. Kobayashi, Yuki
  6. Honda, Kurara
  7. Ishiwata, Mizuho
  8. Ueda, Junko
  9. Hara, Tomonori
  10. Nakanishi, Moe
  11. Takumi, Toru ORCID logo
  12. Itohara, Shigeyoshi
  13. Kuraku, Shigehiro
  14. Asano, Masahide
  15. Kasahara, Takaoki
  16. Nakajima, Kazuo
  17. Tsuboi, Takashi
  18. Takata, Atsushi ORCID logo
  19. Kato, Tadafumi ORCID logo

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1000 Titel
  • Transcriptomic dysregulation and autistic-like behaviors in Kmt2c haploinsufficient mice rescued by an LSD1 inhibitor
1000 Autor/in
  1. Nakamura, Takumi |
  2. Yoshihara, Toru |
  3. Tanegashima, Chiharu |
  4. Kadota, Mitsutaka |
  5. Kobayashi, Yuki |
  6. Honda, Kurara |
  7. Ishiwata, Mizuho |
  8. Ueda, Junko |
  9. Hara, Tomonori |
  10. Nakanishi, Moe |
  11. Takumi, Toru |
  12. Itohara, Shigeyoshi |
  13. Kuraku, Shigehiro |
  14. Asano, Masahide |
  15. Kasahara, Takaoki |
  16. Nakajima, Kazuo |
  17. Tsuboi, Takashi |
  18. Takata, Atsushi |
  19. Kato, Tadafumi |
1000 Verlag Nature Publishing Group UK
1000 Erscheinungsjahr 2024
1000 Publikationstyp
  1. Artikel |
1000 Online veröffentlicht
  • 2024-03-26
1000 Erschienen in
1000 Quellenangabe
  • 29(9):2888-2904
1000 Copyrightjahr
  • 2024
1000 Lizenz
1000 Verlagsversion
  • https://doi.org/10.1038/s41380-024-02479-8 |
  • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11420081/ |
1000 Publikationsstatus
1000 Begutachtungsstatus
1000 Sprache der Publikation
1000 Abstract/Summary
  • <jats:title>Abstract</jats:title><jats:p>Recent studies have consistently demonstrated that the regulation of chromatin and gene transcription plays a pivotal role in the pathogenesis of neurodevelopmental disorders. Among many genes involved in these pathways, <jats:italic>KMT2C</jats:italic>, encoding one of the six known histone H3 lysine 4 (H3K4) methyltransferases in humans and rodents, was identified as a gene whose heterozygous loss-of-function variants are causally associated with autism spectrum disorder (ASD) and the Kleefstra syndrome phenotypic spectrum. However, little is known about how <jats:italic>KMT2C</jats:italic> haploinsufficiency causes neurodevelopmental deficits and how these conditions can be treated. To address this, we developed and analyzed genetically engineered mice with a heterozygous frameshift mutation of <jats:italic>Kmt2c</jats:italic> (<jats:italic>Kmt2c</jats:italic><jats:sup>+/fs</jats:sup> mice) as a disease model with high etiological validity. In a series of behavioral analyses, the mutant mice exhibit autistic-like behaviors such as impairments in sociality, flexibility, and working memory, demonstrating their face validity as an ASD model. To investigate the molecular basis of the observed abnormalities, we performed a transcriptomic analysis of their bulk adult brains and found that ASD risk genes were specifically enriched in the upregulated differentially expressed genes (DEGs), whereas KMT2C peaks detected by ChIP-seq were significantly co-localized with the downregulated genes, suggesting an important role of putative indirect effects of <jats:italic>Kmt2c</jats:italic> haploinsufficiency. We further performed single-cell RNA sequencing of newborn mouse brains to obtain cell type-resolved insights at an earlier stage. By integrating findings from ASD exome sequencing, genome-wide association, and postmortem brain studies to characterize DEGs in each cell cluster, we found strong ASD-associated transcriptomic changes in radial glia and immature neurons with no obvious bias toward upregulated or downregulated DEGs. On the other hand, there was no significant gross change in the cellular composition. Lastly, we explored potential therapeutic agents and demonstrate that vafidemstat, a lysine-specific histone demethylase 1 (LSD1) inhibitor that was effective in other models of neuropsychiatric/neurodevelopmental disorders, ameliorates impairments in sociality but not working memory in adult <jats:italic>Kmt2c</jats:italic><jats:sup>+/fs</jats:sup> mice. Intriguingly, the administration of vafidemstat was shown to alter the vast majority of DEGs in the direction to normalize the transcriptomic abnormalities in the mutant mice (94.3 and 82.5% of the significant upregulated and downregulated DEGs, respectively, <jats:italic>P</jats:italic> &lt; 2.2 × 10<jats:sup>−16</jats:sup>, binomial test), which could be the molecular mechanism underlying the behavioral rescuing. In summary, our study expands the repertoire of ASD models with high etiological and face validity, elucidates the cell-type resolved molecular alterations due to <jats:italic>Kmt2c</jats:italic> haploinsufficiency, and demonstrates the efficacy of an LSD1 inhibitor that might be generalizable to multiple categories of psychiatric disorders along with a better understanding of its presumed mechanisms of action.</jats:p>
1000 Sacherschließung
lokal /38/77
lokal /692/699/476/1373
lokal immediate-communication
lokal Mice, Inbred C57BL [MeSH]
lokal Immediate Communication
lokal /631/337
lokal /38/91
lokal /38/39
lokal /38/61
lokal Autistic Disorder/genetics [MeSH]
lokal Male [MeSH]
lokal Chromosome Deletion [MeSH]
lokal Behavior, Animal [MeSH]
lokal Disease Models, Animal [MeSH]
lokal Female [MeSH]
lokal Heart Defects, Congenital [MeSH]
lokal Histone-Lysine N-Methyltransferase/genetics [MeSH]
lokal /631/208
lokal Chromosomes, Human, Pair 9 [MeSH]
lokal Transcriptome/genetics [MeSH]
lokal /631/154
lokal Intellectual Disability/genetics [MeSH]
lokal Animals [MeSH]
lokal Histone-Lysine N-Methyltransferase/metabolism [MeSH]
lokal /64/60
lokal /38/70
lokal Mice [MeSH]
lokal Brain/metabolism [MeSH]
lokal Haploinsufficiency/genetics [MeSH]
lokal Histone Demethylases/genetics [MeSH]
lokal Autism Spectrum Disorder/genetics [MeSH]
lokal Craniofacial Abnormalities/genetics [MeSH]
lokal Histone Demethylases/metabolism [MeSH]
lokal /631/378
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  1. https://orcid.org/0000-0002-5611-6534|https://frl.publisso.de/adhoc/uri/WW9zaGloYXJhLCBUb3J1|https://frl.publisso.de/adhoc/uri/VGFuZWdhc2hpbWEsIENoaWhhcnU=|https://frl.publisso.de/adhoc/uri/S2Fkb3RhLCBNaXRzdXRha2E=|https://frl.publisso.de/adhoc/uri/S29iYXlhc2hpLCBZdWtp|https://frl.publisso.de/adhoc/uri/SG9uZGEsIEt1cmFyYQ==|https://frl.publisso.de/adhoc/uri/SXNoaXdhdGEsIE1penVobw==|https://frl.publisso.de/adhoc/uri/VWVkYSwgSnVua28=|https://frl.publisso.de/adhoc/uri/SGFyYSwgVG9tb25vcmk=|https://frl.publisso.de/adhoc/uri/TmFrYW5pc2hpLCBNb2U=|https://orcid.org/0000-0001-7153-266X|https://frl.publisso.de/adhoc/uri/SXRvaGFyYSwgU2hpZ2V5b3NoaQ==|https://frl.publisso.de/adhoc/uri/S3VyYWt1LCBTaGlnZWhpcm8=|https://frl.publisso.de/adhoc/uri/QXNhbm8sIE1hc2FoaWRl|https://frl.publisso.de/adhoc/uri/S2FzYWhhcmEsIFRha2Fva2k=|https://frl.publisso.de/adhoc/uri/TmFrYWppbWEsIEthenVv|https://frl.publisso.de/adhoc/uri/VHN1Ym9pLCBUYWthc2hp|https://orcid.org/0000-0002-0928-4586|https://orcid.org/0000-0001-7856-3952
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  1. Japan Agency for Medical Research and Development |
  2. Japan Society for the Promotion of Science |
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