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Project description:Deficits in Schwann cell-mediated remyelination impair functional restoration after nerve damage, contributing to peripheral neuropathies. The mechanisms mediating block of remyelination remain elusive. Here, through small-molecule screening focusing on epigenetic modulators, we identified histone deacetylase 3 (HDAC3; a histone-modifying enzyme) as a potent inhibitor of peripheral myelinogenesis. Inhibition of HDAC3 enhanced myelin growth and regeneration and improved functional recovery after peripheral nerve injury in mice. HDAC3 antagonizes the myelinogenic neuregulin-PI3K-AKT signaling axis. Moreover, genome-wide profiling analyses revealed that HDAC3 represses promyelinating programs through epigenetic silencing while coordinating with p300 histone acetyltransferase to activate myelination-inhibitory programs that include the HIPPO signaling effector TEAD4 to inhibit myelin growth. Schwann cell-specific deletion of either Hdac3 or Tead4 in mice resulted in an elevation of myelin thickness in sciatic nerves. Thus, our findings identify the HDAC3-TEAD4 network as a dual-function switch of cell-intrinsic inhibitory machinery that counters myelinogenic signals and maintains peripheral myelin homeostasis, highlighting the therapeutic potential of transient HDAC3 inhibition for improving peripheral myelin repair.
| S-EPMC5908710 | biostudies-literature
Project description:Schwann cell remyelination defects impair functional restoration after nerve damage, contributing to peripheral neuropathies. The mechanisms that mediate remyelination block remain elusive. Upon small-molecule epigenetic screening, we identified HDAC3, a histone-modifying enzyme, as a potent inhibitor of peripheral myelinogenesis. Inhibition of HDAC3 markedly enhances myelin growth and regeneration, and improves functional recovery after peripheral nerve injury. HDAC3 antagonizes myelinogenic neuregulin/PI3K/AKT signaling axis. Moreover, genome-wide profiling analyses reveal that HDAC3 represses pro-myelinating programs through epigenetic silencing, while coordinating with p300 histone acetyltransferase to activate myelination-inhibitory programs that include HIPPO signaling effector TEAD4 to inhibit myelin growth. Schwann-cell-specific deletion of either Hdac3 or Tead4 results in a profound increase in myelin thickness in sciatic nerves. Thus, our findings identify the HDAC3-TEAD4 network as a dual-function switch of cell-intrinsic inhibitory machinery that counters myelinogenic signals and maintains peripheral myelin homeostasis, highlighting the therapeutic potential of transient HDAC3 inhibition for improving peripheral myelin repair.
2018-02-11 | GSE93160 | GEO
Project description:Schwann cell remyelination defects impair functional restoration after nerve damage, contributing to peripheral neuropathies. The mechanisms that mediate remyelination block remain elusive. Upon small-molecule epigenetic screening, we identified HDAC3, a histone-modifying enzyme, as a potent inhibitor of peripheral myelinogenesis. Inhibition of HDAC3 markedly enhances myelin growth and regeneration, and improves functional recovery after peripheral nerve injury. HDAC3 antagonizes myelinogenic neuregulin/PI3K/AKT signaling axis. Moreover, genome-wide profiling analyses reveal that HDAC3 represses pro-myelinating programs through epigenetic silencing, while coordinating with p300 histone acetyltransferase to activate myelination-inhibitory programs that include HIPPO signaling effector TEAD4 to inhibit myelin growth. Schwann-cell-specific deletion of either Hdac3 or Tead4 results in a profound increase in myelin thickness in sciatic nerves. Thus, our findings identify the HDAC3-TEAD4 network as a dual-function switch of cell-intrinsic inhibitory machinery that counters myelinogenic signals and maintains peripheral myelin homeostasis, highlighting the therapeutic potential of transient HDAC3 inhibition for improving peripheral myelin repair.
2018-02-11 | GSE93159 | GEO
Project description:A Histone Deacetylase 3-Dependent Pathway Delimits Peripheral Myelin Growth and Functional Regeneration
| PRJNA360157 | ENA
Project description:Observing the structure and regeneration of the myelin sheath in peripheral nerves following injury and during repair would help in understanding the pathogenesis and treatment of neurological diseases caused by an abnormal myelin sheath. In the present study, transmission electron microscopy, immunofluorescence staining, and transcriptome analyses were used to investigate the structure and regeneration of the myelin sheath after end-to-end anastomosis, autologous nerve transplantation, and nerve tube transplantation in a rat model of sciatic nerve injury, with normal optic nerve, oculomotor nerve, sciatic nerve, and Schwann cells used as controls. The results suggested that the double-bilayer was the structural unit that constituted the myelin sheath. The major feature during regeneration was the compaction of the myelin sheath, wherein the distance between the 2 layers of cell membrane in the double-bilayer became shorter and the adjacent double-bilayers tightly closed together and formed the major dense line. The expression level of myelin basic protein was positively correlated with the formation of the major dense line, and the compacted myelin sheath could not be formed without the anchoring of the lipophilin particles to the myelin sheath.
| S-EPMC6825268 | biostudies-literature
Project description:The successful removal of damaged myelin sheaths during Wallerian degeneration (WD) is essential for ensuring structural remodelling and functional recovery following traumatic peripheral nerve injury (PNI). Recent studies have established that autophagy involves myelin phagocytosis and cellular homoeostasis, and its disorder impairs myelin clearance. Based on the role of basic fibroblast growth factor (bFGF) on exerting neuroprotection and angiogenesis during nerve tissue regeneration, we now explicitly focus on the issue about whether the therapeutic effect of bFGF on supporting nerve regeneration is closely related to accelerate the autophagic clearance of myelin debris during WD. Using sciatic nerve crushed model, we found that bFGF remarkedly improved axonal outgrowth and nerve reconstruction at the early phase of PNI (14 days after PNI). More importantly, we further observed that bFGF could enhance phagocytic capacity of Schwann cells (SCs) to engulf myelin debris. Additionally, this enhancing effect is accomplished by autophagy activation and the increase of autophagy flux by immunoblotting and immune-histochemical analyses. Taken together, our data suggest that the action of bFGF on modulating early peripheral nerve regeneration is closely associated with myelin debris removal by SCs, which might result in SC-mediated autophagy activation, highlighting its insight molecular mechanism as a neuroprotective agent for repairing PNI.
| S-EPMC7933946 | biostudies-literature
Project description:Class IIa histone deacetylases (HDACs) are critical transcriptional regulators, shuttling between nuclear and cytoplasmic cellular compartments. Within the nucleus, these HDACs repress transcription as components of multiprotein complexes, such as the nuclear corepressor and beclin-6 corepressor (BCoR) complexes. Cytoplasmic relocalization relieves this transcriptional repressive function. Class IIa HDAC shuttling is controlled, in part, by phosphorylations flanking the nuclear localization signal (NLS). Furthermore, we have reported that phosphorylation within the NLS by the kinase Aurora B modulates the localization and function of the class IIa HDAC5 during mitosis. While we identified numerous additional HDAC5 phosphorylations, their regulatory functions remain unknown. Here, we studied phosphorylation sites within functional HDAC5 domains, including the deacetylation domain (DAC, Ser755), nuclear export signal (NES, Ser1108), and an acidic domain (AD, Ser611). We have generated phosphomutant cell lines to investigate how absence of phosphorylation at these sites impacts HDAC5 localization, enzymatic activity, and protein interactions. Combining molecular biology and quantitative MS, we have defined the interactions and HDAC5-containing complexes mediated by site-specific phosphorylation and quantified selected changes using parallel reaction monitoring. These results expand the current understanding of HDAC regulation, and the functions of this critical family of proteins within human cells.
| S-EPMC4184959 | biostudies-literature
Project description:Histone deacetylase (HDAC) proteins are promising targets for cancer treatment, as shown by the recent FDA approval of the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA, Vorinostat) for the treatment of cutaneous T-cell lymphoma. To identify additional potent inhibitors and characterize HDAC mutant proteins, there is interest to develop an inexpensive screening method dependent on native substrates. Here, we report the first yeast-based gene reporter screen dependent on the yeast Rpd3, which is a homolog of human class I HDAC proteins. The screen was sensitive to an inactive Rpd3 mutant and various inhibitors in qualitative, agar-based and quantitative, solution-phase formats. Interestingly, inclusion of the lytic enzyme zymolyase enhanced the inhibitor sensitivity of the screen. The gene reporter screen provides a tool to screen Rpd3 mutants and inhibitors of class I HDAC proteins.
| S-EPMC3033752 | biostudies-literature
Project description:Stress and glucocorticoid (GC) release are common behavioral and hormonal responses to injury or disease. In the brain, stress/GCs can alter neuron structure and function leading to cognitive impairment. Stress and GCs also exacerbate pain, but whether a corresponding change occurs in structural plasticity of sensory neurons is unknown. Here, we show that in female mice (Mus musculus) basal GC receptor (Nr3c1, also known as GR) expression in dorsal root ganglion (DRG) sensory neurons is 15-fold higher than in neurons in canonical stress-responsive brain regions (M. musculus). In response to stress or GCs, adult DRG neurite growth increases through mechanisms involving GR-dependent gene transcription. In vivo, prior exposure to an acute systemic stress increases peripheral nerve regeneration. These data have broad clinical implications and highlight the importance of stress and GCs as novel behavioral and circulating modifiers of neuronal plasticity.
| S-EPMC5563843 | biostudies-other
Project description:Candida albicans is a mucosal commensal organism capable of causing superficial (oral and vaginal thrush) infections in immune normal hosts, but is a major pathogen causing systemic and mucosal infections in immunocompromised individuals. Azoles have been very effective anti-fungal agents and the mainstay in treating opportunistic mold and yeast infections. Azole resistant strains have emerged compromising the utility of this class of drugs. It has been shown that azole resistance can be reversed by the co-administration of a histone deacetylase (HDAC) inhibitor, suggesting that resistance is mediated by epigenetic mechanisms possibly involving Hos2, a fungal deacetylase. We report here the cloning and functional characterization of HOS2 (High Osmolarity Sensitive) , a gene coding for fungal histone deacetylase from C. albicans. Inhibition studies showed that Hos2 is susceptible to pan inhibitors such as trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA), but is not inhibited by class I inhibitors such as MS-275. This in vitro enzymatic assay, which is amenable to high throughput could be used for screening potent fungal Hos2 inhibitors that could be a potential anti-fungal adjuvant. Purified Hos2 protein consistently deacetylated tubulins, rather than histones from TSA-treated cells. Hos2 has been reported to be a putative NAD+ dependent histone deacetylase, a feature of sirtuins. We assayed for sirtuin activation with resveratrol and purified Hos2 protein and did not find any sirtuin activity.
| S-EPMC4111124 | biostudies-literature