SETD5 Regulates Chromatin Methylation State and Preserves Global Transcriptional Fidelity during Brain Development and Neuronal Wiring

Alessandro Sessa, Luca Fagnocchi, Giuseppina Mastrototaro, Luca Massimino, Mattia Zaghi, Marzia Indrigo, Stefano Cattaneo, Davide Martini, Chiara Gabellini, Cecilia Pucci, Alessandra Fasciani, Romina Belli, Stefano Taverna, Massimiliano Andreazzoli, Alessio Zippo, Vania Broccoli

Research output: Contribution to journalArticle

Abstract

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 haploinsufficiency 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.

Original languageEnglish
Pages (from-to)271-289.e13
JournalNeuron
Volume104
Issue number2
DOIs
Publication statusPublished - Oct 23 2019

    Fingerprint

Keywords

  • autism spectrum disorders
  • epigenetics
  • intellectual disability
  • neural development
  • SETD5

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Sessa, A., Fagnocchi, L., Mastrototaro, G., Massimino, L., Zaghi, M., Indrigo, M., Cattaneo, S., Martini, D., Gabellini, C., Pucci, C., Fasciani, A., Belli, R., Taverna, S., Andreazzoli, M., Zippo, A., & Broccoli, V. (2019). SETD5 Regulates Chromatin Methylation State and Preserves Global Transcriptional Fidelity during Brain Development and Neuronal Wiring. Neuron, 104(2), 271-289.e13. https://doi.org/10.1016/j.neuron.2019.07.013