The Autism-Related Protein SETD5 Controls Neural Cell Proliferation through Epigenetic Regulation of rDNA Expression
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Haploinsufficiency of SETD5 is implicated in syndromic autism spectrum disorder (ASD), but the molecular mechanism underlying the pathological role of this protein has remained unclear. We have now shown that Setd5 +/– mice manifest ASD-related behavioral phenotypes and that the expression of ribosomal protein genes and rDNA is disturbed in the brain of these mice. SETD5 recruited the HDAC3 complex to the rDNA promoter, resulting in removal of the histone mark H4K16ac and its reader protein TIP5, a repressor of rDNA expression. Depletion of SETD5 attenuated rDNA expression, translational activity, and neural cell proliferation, whereas ablation of TIP5 in SETD5-deficient cells rescued these effects. Translation of cyclin D1 mRNA was specifically down-regulated in SETD5-insufficient cells. Our results thus suggest that SETD5 positively regulates rDNA expression via an HDAC3-mediated epigenetic mechanism and that such regulation is essential for translation of cyclin D1 mRNA and neural cell proliferation.
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Notable perturbation-specific gene ontology terms include ribosome assembly (SETD5), mitochondrion organization (FOXP1), lipid homoeostasis (IRF2BPL), autophagosome maturation (KAT2B), and cilium development (MECP2).
“Some notable examples include the gene ontology terms ribosome assembly (SETD5 perturbation)36, mitochondrion organization (FOXP1 perturbation)37, lipid homoeostasis (IRF2BPL perturbation)38, autophagosome maturation (KAT2B perturbation)39 and cilium development (MECP2 perturbation)40.”
From Single-cell brain organoid screening identifies developmental defects in autism (2023) · cites this paper as [36]
The Results section, “Impaired Expression of Ribosome-Related Genes in the Setd5+/– Mouse Brain” (page unavailable), reports GO enrichment of ribosomal-protein genes among genes down-regulated after SETD5 reduction. It also discusses ribosome assembly, but does not identify “ribosome assembly” as an enriched GO term. The other gene–term pairs have separate citations and are not attributed to this source. (LLM, conf=0.84)
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Cited by
Sorted by citations
Single-cell brain organoid screening identifies developmental defects in autism
Li, C., Fleck, J. S., Martins-Costa, C., Burkard, T. R., Themann, J., Stuempflen, M., Peer, A. M., Vertesy, Á., Littleboy, J. B., Esk, C., et al. (2023) · Nature · doi:10.1038/s41586-023-06473-y · Cited by 283 · see citing works
- Authors
- Nakagawa, T., Hattori, S., Nobuta, R., Kimura, R., Nakagawa, M., Matsumoto, M., Nagasawa, Y., Funayama, R., Miyakawa, T., Inada, T., Osumi, N., Nakayama, K. I., & Nakayama, K.
- Affiliations
- Tohoku University (JP)
- Fujita Health University (JP)
- Kyushu University (JP)
- Corresponding author
- Nakayama, Keiko
- ORCID
- Venue
- iScience
- Publisher
- Elsevier BV
- Published
- 2020-04
- Volume
- 23
- Issue
- 4
- Pages
- 101030
- ISSN
- 2589-0042 (ISSN-L)
- PMC
- PMC7160574
- OpenAlex
- W3015736762
- Cited by
- 27
- References
- 6
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 4 · 2023: 9 · 2022: 5 · 2021: 3 · 2020: 1
- FWCI
- 2.64
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- iScience (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Japan Society for the Promotion of Science (15K18365, JP16H06276, 17H04035, 17K14955, 19K07837)
- Ministry of Education, Culture, Sports, Science and Technology
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Keywords
- SETD5, autism spectrum disorder, haploinsufficiency, ribosomal protein genes, neural cell proliferation, HDAC3, epigenetic regulation, protein synthesis inhibition
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