Journal
NEURON
Volume 104, Issue 2, Pages 271-+Publisher
CELL PRESS
DOI: 10.1016/j.neuron.2019.07.013
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Funding
- Telethon [GGP15096, GGP16234B]
- Italian Ministry of Health [GR-2013-02355540, GR-2011-02351172]
- Italian Ministry of Instruction, University, and Research (PRIN2017) [2017M95WBA]
- European Regional Development Fund (ERDF) 2014-2020
- Federazione Italiana Sclerosi Multipla [FISM - 2015/R/24]
- Fondazione Veronesi
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Mutations in one SETD5 allele are genetic causes of intellectual disability and autistic spectrum disorders. However, the mechanisms by which SETD5 regulates brain development and function remain largely elusive. Herein, we found that Setd5 haploin-sufficiency impairs the proliferative dynamics of neural progenitors and synaptic wiring of neurons, ultimately resulting in behavioral deficits in mice. Mechanistically, Setd5 inactivation in neural stem cells, zebrafish, and mice equally affects genome-wide levels of H3K36me3 on active gene bodies. Notably, we demonstrated that SETD5 directly deposits H3K36me3, which is essential to allow on-time RNA elongation dynamics. Hence, Setd5 gene loss leads to abnormal transcription, with impaired RNA maturation causing detrimental effects on gene integrity and splicing. These findings identify SETD5 as a fundamental epigenetic enzyme controlling the transcriptional landscape in neural progenitors and their derivatives and illuminate the molecular events that connect epigenetic defects with neuronal dysfunctions at the basis of related human diseases.
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