Matheos, D. P. | Search bioRxiv

bioRxiv2018

PP4-dependent HDAC3 dephosphorylation discriminates between axonal regeneration and regenerative failure

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.\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=122 SRC=\"FIGDIR/small/446963_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (40K):\norg.highwire.dtl.DTLVardef@1bd577corg.highwire.dtl.DTLVardef@1ba990aorg.highwire.dtl.DTLVardef@195813corg.highwire.dtl.DTLVardef@57abc7_HPS_FORMAT_FIGEXP M_FIG Graphical AbstractFollowing central nervous system (CNS) spinal injury, protein phosphatase 4/2 activity is not induced since calcium levels remain unchanged compared to uninjured conditions. HDAC3 remains phosphorylated and occupies deacetylated chromatin contributing to its compaction inhibiting gene expression. Following peripheral nervous system (PNS) sciatic injury, protein phosphatase 4/2 activity is induced by calcium. HDAC3 is dephosphorylated leading to its inhibition and release from chromatin sites contributing to increase in histone acetylation and in the expression of regeneration associated genes (RAGs).\n\nC_FIG

neuroscience↗

bioRxiv2018

Epigenetic regulation of the circadian gene Per1 in the hippocampus mediates age-related changes in memory and synaptic plasticity

Aging is accompanied by impairments in both circadian rhythmicity and long-term memory. Although it is clear that memory performance is affected by circadian cycling, it is unknown whether age-related disruption of the circadian clock causes impaired hippocampal memory. Here, we show that the repressive histone deacetylase HDAC3 restricts long-term memory, synaptic plasticity, and learning-induced expression of the circadian gene Per1 in the aging hippocampus without affecting rhythmic circadian activity patterns. We also demonstrate that hippocampal Per1 is critical for long-term memory formation. Together, our data challenge the traditional idea that alterations in the core circadian clock drive circadian-related changes in memory formation and instead argue for a more autonomous role for circadian clock gene function in hippocampal cells to gate the likelihood of long-term memory formation.

neuroscience↗

bioRxiv2017

Habits are negatively regulated by HDAC3 in the dorsal striatum

Optimal behavior results from a balance of control between two strategies, one cognitive/goal-directed and one habitual, which rely on the anatomically distinct dorsomedial (DMS) and dorsolateral (DLS) striatum, respectively. The transcriptional regulatory mechanisms required to learn and transition between these strategies are unknown. Here we identified a critical negative regulator of habit learning. Histone deacetylase (HDAC) inhibition following instrumental conditioning accelerated habitual control of behavior. HDAC3, a transcriptional repressor, was removed from the promoters of learning-related genes in the dorsal striatum as habits formed with overtraining and with post-training HDAC inhibition. Decreasing HDAC3 function in the DLS accelerated habit formation, while DLS HDAC3 overexpression prevented habit. HDAC3 activity in the DMS was also found to constrain habit formation. These results challenge the strict dissociation between DMS and DLS function in goal-directed v. habitual behavioral control and identify dorsal striatal HDAC3 as a critical molecular substrate of the transition to habit.

neuroscience↗