PP4-dependent HDAC3 dephosphorylation discriminates between axonal regeneration and regenerative failure.
Animals
Axons
Cells, Cultured
Disease Models, Animal
Epigenesis, Genetic
/ drug effects
Female
Ganglia, Spinal
/ physiology
Histone Deacetylases
/ metabolism
Male
Mice
Nerve Regeneration
Peripheral Nerve Injuries
/ metabolism
Phosphoprotein Phosphatases
/ metabolism
Phosphorylation
/ drug effects
Signal Transduction
Small Molecule Libraries
/ pharmacology
HDAC3
calcium
nerve regeneration
spinal cord injury
transcription
Journal
The EMBO journal
ISSN: 1460-2075
Titre abrégé: EMBO J
Pays: England
ID NLM: 8208664
Informations de publication
Date de publication:
01 07 2019
01 07 2019
Historique:
received:
29
10
2018
revised:
15
04
2019
accepted:
17
04
2019
entrez:
4
7
2019
pubmed:
4
7
2019
medline:
24
12
2019
Statut:
ppublish
Résumé
The molecular mechanisms discriminating between regenerative failure and success remain elusive. While a regeneration-competent peripheral nerve injury mounts a regenerative gene expression response in bipolar dorsal root ganglia (DRG) sensory neurons, a regeneration-incompetent central spinal cord injury does not. This dichotomic response offers a unique opportunity to investigate the fundamental biological mechanisms underpinning regenerative ability. Following a pharmacological screen with small-molecule inhibitors targeting key epigenetic enzymes in DRG neurons, we identified HDAC3 signalling as a novel candidate brake to axonal regenerative growth. In vivo, we determined that only a regenerative peripheral but not a central spinal injury induces an increase in calcium, which activates protein phosphatase 4 that in turn dephosphorylates HDAC3, thus impairing its activity and enhancing histone acetylation. Bioinformatics analysis of ex vivo H3K9ac ChIPseq and RNAseq from DRG followed by promoter acetylation and protein expression studies implicated HDAC3 in the regulation of multiple regenerative pathways. Finally, genetic or pharmacological HDAC3 inhibition overcame regenerative failure of sensory axons following spinal cord injury. Together, these data indicate that PP4-dependent HDAC3 dephosphorylation discriminates between axonal regeneration and regenerative failure.
Identifiants
pubmed: 31268609
doi: 10.15252/embj.2018101032
pmc: PMC6600644
doi:
Substances chimiques
Small Molecule Libraries
0
Phosphoprotein Phosphatases
EC 3.1.3.16
protein phosphatase 4
EC 3.1.3.16
Histone Deacetylases
EC 3.5.1.98
histone deacetylase 3
EC 3.5.1.98
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e101032Subventions
Organisme : Henry Smith Charity
Pays : International
Organisme : Medical Research Council
ID : MR/T003111/1
Pays : United Kingdom
Organisme : the Spanish Ministry of Economy, Industry and Competitiveness
ID : IJCI-2016-30783
Pays : International
Organisme : Wings for Life (Wings for Life United Kingdom)
Pays : International
Organisme : Imperial Biomedical Research Centre (SDG)
Pays : International
Organisme : the Spanish Ministry of Economy, Industry and Competitiveness
ID : BFU2015-67777-R
Pays : International
Organisme : National Institute for Health Research (NIHR)
Pays : International
Organisme : Medical Research Council
ID : MR/R005311/1
Pays : United Kingdom
Organisme : Rosetrees Trust
Pays : International
Informations de copyright
© 2019 The Authors.
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