PUBLICATION
SETD5 Regulates Chromatin Methylation State and Preserves Global Transcriptional Fidelity during Brain Development and Neuronal Wiring
- Authors
- 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.
- ID
- ZDB-PUB-190914-1
- Date
- 2019
- Source
- Neuron 104(2): 271-289.e13 (Journal)
- Registered Authors
- Andreazzoli, Massimiliano
- Keywords
- SETD5, autism spectrum disorders, epigenetics, intellectual disability, neural development
- MeSH Terms
-
- Brain/embryology*
- Brain/metabolism
- Zebrafish
- RNA-Seq
- Social Behavior
- Neural Stem Cells/metabolism
- Histone Methyltransferases/genetics
- Gene Expression Regulation, Developmental/genetics*
- Zebrafish Proteins/genetics
- Methyltransferases/genetics*
- Animals
- Cognition
- Epigenesis, Genetic
- Mice
- Chromatin Immunoprecipitation Sequencing
- Mutation
- Chromatin/metabolism*
- Transcription Elongation, Genetic
- RNA Splicing/genetics
- Histone Code/genetics*
- Behavior, Animal
- PubMed
- 31515109 Full text @ Neuron
Citation
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.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping