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
  • Behavior, Animal
  • Neural Stem Cells/metabolism
  • Transcription Elongation, Genetic
  • Zebrafish
  • Brain/embryology*
  • Brain/metabolism
  • Histone Methyltransferases/genetics
  • Gene Expression Regulation, Developmental/genetics*
  • Animals
  • Cognition
  • Epigenesis, Genetic
  • Mice
  • Histone Code/genetics*
  • Methyltransferases/genetics*
  • Chromatin Immunoprecipitation Sequencing
  • Mutation
  • RNA Splicing/genetics
  • Social Behavior
  • Zebrafish Proteins/genetics
  • Chromatin/metabolism*
  • RNA-Seq
(all 21)
PubMed
31515109 Full text @ Neuron
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
Figures
Figure Gallery (1 images)
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Expression
Phenotype
Fish Conditions Stage Phenotype Figure
WT + MO2-setd5standard conditionsLong-pec
WT + MO2-setd5standard conditionsLong-pec
WT + MO2-setd5standard conditionsLong-pec
WT + MO2-setd5standard conditionsDay 5
1 - 4 of 4
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Mutations / Transgenics
No data available
Human Disease / Model
Human Disease Fish Conditions Evidence
autism spectrum disorderTAS
1 - 1 of 1
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Sequence Targeting Reagents
Target Reagent Reagent Type
setd5MO2-setd5MRPHLNO
1 - 1 of 1
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Fish
Fish
WT
WT + MO2-setd5
1 - 2 of 2
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Antibodies
No data available
Orthology
Gene Orthology
setd5
1 - 1 of 1
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Engineered Foreign Genes
No data available
Mapping
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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.