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Jun O-GlcNAcylatSchwann cell O-GlcNAcylation promotes peripheral nerve remyelination via attenuation of the AP-1 transcription factor JUNion promotes peripheral nerve remyelination after nerve injury

ABSTRACT: To uncover abnormally regulated genes in OGT-KO SCs, we performed gene expression profiling experiments using sciatic nerves from 1-month-old OGT-SCKO and wildtype mice.

ORGANISM(S): Mus musculus

PROVIDER: GSE115333 | GEO | 2018/06/06

REPOSITORIES: GEO

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Schwann cell O-GlcNAcylation promotes peripheral nerve remyelination via attenuation of the AP-1 transcription factor JUN.

Project description:Schwann cells (SCs), the glia of the peripheral nervous system, play an essential role in nerve regeneration. Upon nerve injury, SCs are reprogrammed into unique "repair SCs," and these cells remove degenerating axons/myelin debris, promote axonal regrowth, and ultimately remyelinate regenerating axons. The AP-1 transcription factor JUN is promptly induced in SCs upon nerve injury and potently mediates this injury-induced SC plasticity; however, the regulation of these JUN-dependent SC injury responses is unclear. Previously, we produced mice with a SC-specific deletion of O-GlcNAc transferase (OGT). This enzyme catalyzes O-GlcNAcylation, a posttranslational modification that is influenced by the cellular metabolic state. Mice lacking OGT in SCs develop a progressive demyelinating peripheral neuropathy. Here, we investigated the nerve repair process in OGT-SCKO mutant mice and found that the remyelination of regenerating axons is severely impaired. Gene expression profiling of OGT-SCKO SCs revealed that the JUN-dependent SC injury program was elevated in the absence of injury and failed to shut down at the appropriate time after injury. This aberrant JUN activity results in abnormalities in repair SC function and redifferentiation and prevents the timely remyelination. This aberrant nerve injury response is normalized in OGT-SCKO mice with reduced Jun gene dosage in SCs. Mechanistically, OGT O-GlcNAcylates JUN at multiple sites, which then leads to an attenuation of AP-1 transcriptional activity. Together, these results highlight the metabolic oversight of the nerve injury response via the regulation of JUN activity by O-GlcNAcylation, a pathway that could be important in the neuropathy associated with diabetes and aging.

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Jun O-GlcNAcylatSchwann cell O-GlcNAcylation promotes peripheral nerve remyelination via attenuation of the AP-1 transcription factor JUNion promotes peripheral nerve remyelination after nerve injury

Project description:Jun O-GlcNAcylatSchwann cell O-GlcNAcylation promotes peripheral nerve remyelination via attenuation of the AP-1 transcription factor JUNion promotes peripheral nerve remyelination after nerve injury

| PRJNA474599 | ENA

4-Aminopyridine promotes functional recovery and remyelination in acute peripheral nerve injury.

Project description:Traumatic peripheral nerve damage is a major medical problem without effective treatment options. In repurposing studies on 4-aminopyridine (4-AP), a potassium channel blocker that provides symptomatic relief in some chronic neurological afflictions, we discovered this agent offers significant promise as a small molecule regenerative agent for acute traumatic nerve injury. We found, in a mouse model of sciatic crush injury, that sustained early 4-AP administration increased the speed and extent of behavioral recovery too rapidly to be explained by axonal regeneration. Further studies demonstrated that 4-AP also enhanced recovery of nerve conduction velocity, promoted remyelination, and increased axonal area post-injury. We additionally found that 4-AP treatment enables distinction between incomplete and complete lesions more rapidly than existing approaches, thereby potentially addressing the critical challenge of more effectively distinguishing injured individuals who may require mutually exclusive treatment approaches. Thus, 4-AP singularly provides both a new potential therapy to promote durable recovery and remyelination in acute peripheral nerve injury and a means of identifying lesions in which this therapy would be most likely to be of value.

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H3K27 trimethylation in mouse peripheral nerve

Project description:ChIP-seq of H3K27 trimethylation in sciatic nerve

2015-04-01 | GSE64260 | GEO

H3K27 trimethylation in mouse peripheral nerve

Project description:ChIP-seq of H3K27 trimethylation in sciatic nerve H3K27me3 ChIP-Seq with corresponding input

2015-04-01 | E-GEOD-64260 | biostudies-arrayexpress

Enhancer Analysis in Peripheral Nerve: ChIP-seq of H3K27ac in P15 sciatic nerve

Project description:ChIP-seq of H3K27ac in P15 sciatic nerve 1 H3K27ac ChIP sample, with respective input

2015-04-01 | E-GEOD-64971 | biostudies-arrayexpress

Enhancer Analysis in Peripheral Nerve Injury

Project description:ChIP-seq of H3K27acetylation in sham and injured nerve. Schwann cells play an important role in the response of peripheral nerve to injury. This study was designed to identify enhancers that are altered in sciatic nerve at 3 days post-injury to help identify pathways that mediate the gene expression reprogramming that occurs in Schwann cells after nerve injury. We employed ChIP-seq analysis of H3K27 acetylation as a mark of actively engaged enhancers, and compared enhancers in the distal stump of transected sciatic nerve compared to contralateral (sham) condition.

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KIF1A promotes neuroendocrine differentiation in prostate cancer by regulating the OGT-mediated O-GlcNAcylation

Project description:Background: Treatment-related neuroendocrine prostate cancer (t-NEPC) is a highly aggressive form of prostate cancer (PCa). Understanding the molecular mechanisms driving t-NEPC may provide valuable therapeutic strategies. Methods: we performed a pan-cancer differential mRNA abundance analysis of neuroendocrine tumors (NET) and non-NETs using integrated datasets to identify potential driver genes in NEPC. Gain- and loss-of-function studies were performed in PCa cell lines and subcutaneous xenografts in mouse to characterize the role of Kinesin-like protein (KIF1A) in neuroendocrine (NE) differentiation. Western blot, qRT-PCR, immunoprecipitation (IP), nuclear and cytoplasmic protein extraction, CO-IP and immunofluorescence were performed to study the regulation of KIF1A to OGT. Results: We identified that KIF1A overexpression is highly correlated to NE differentiation. NE differentiation features in PCa, including NE marker gene expression, stemness and EMT, were impaired by KIF1A knockdown and promoted by KIF1A overexpression. Targeting KIF1A inhibited the growth of NE-differentiated PCa cells in vitro and in vivo. Mechanistically, KIF1A bound with OGT and regulated its protein expression and O-linked N-acetylglucosamine transferase activity. OGT nuclear translocation induced by elevated KIF1A inhibited OGT ubiquitin-proteasome pathway degradation in the cytoplasm and promoted intranuclear O-GlcNAcylation of β-catenin and OCT4. More importantly, our data revealed that OGT is critical for KIF1A induced NE differentiation and aggressive growth. Conclusion: KIF1A promotes NE differentiation through modeling OGT O-GlcNAcylation in PCa. Targeting KIF1A - OGT may impede the development of NEPC for a group of PCa patients with elevated KIF1A expression.

2024-10-23 | GSE266283 | GEO

TET2 and TET3 regulate GlcNAcylation and H3K4 methylation through OGT and SET1/COMPASS

Project description:TET proteins convert 5-methylcytosine to 5-hydroxymethylcytosine, an emerging dynamic epigenetic state of DNA that can influence transcription. Evidence has linked TET1 function to epigenetic repression complexes, yet mechanistic information, especially for the TET2 and TET3 proteins, remains limited. Here, we show a direct interaction of TET2 and TET3 with O-GlcNAc transferase (OGT). OGT does not appear to influence hmC activity, rather TET2 and TET3 promote OGT activity. TET2/3-OGT co-localize on chromatin at active promoters enriched for H3K4me3 and reduction of either TET2/3 or OGT activity results in a direct decrease in H3K4me3 and concomitant decreased transcription. Further, we show that Host Cell Factor 1 (HCF1), a component of the H3K4 methyltransferase SET1/COMPASS complex, is a specific GlcNAcylation target of TET2/3-OGT, and modification of HCF1 is important for the integrity of SET1/COMPASS. Additionally, we find both TET proteins and OGT activity promote binding of the SET1/COMPASS H3K4 methyltransferase, SETD1A, to chromatin. Finally, studies in Tet2 knockout mouse bone marrow tissue extend and support the data as decreases are observed of global GlcNAcylation and also of H3K4me3, notably at several key regulators of haematopoiesis. Together, our results unveil a step-wise model, involving TET-OGT interactions, promotion of GlcNAcylation, and influence on H3K4me3 via SET1/COMPASS, highlighting a novel means by which TETs may induce transcriptional activation. ChIP-Seq experiments were performed on Illumina HiScanSQ sequencer in wild-type HEK293T cells for H3K4me3 histone marks, O-GlcNAc and HCF1, for HT-TET2, HT-TET3 and HT-OGT in HEK293T cells overexpressing those three fusion proteins and in TET2 Kd HEK293T cells for H3K4me3 histone marks. ChIP-Seqs were also performed in mouse bone marrow tissues for H3K4me3 histone marks, O-GlcNAc, endogenous Tet2 and in Tet2 Ko bone marrow tissues for H3K4me3 histone marks.

2013-02-07 | E-GEOD-36620 | biostudies-arrayexpress

Enhancer Analysis in Peripheral Nerve: ChIP-seq of H3K27ac in P15 sciatic nerve

Project description:ChIP-seq of H3K27ac in P15 sciatic nerve was used to identify actively engaged enhancers in Schwann cells, which constitute the majority of nuclei in peripheral nerve.

2015-04-01 | GSE64971 | GEO

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