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Dor regulates alpha-KG metabolic pathways in mature oligodendrocytes to enhance myelination and reverse age-related remyelination decline [CUT&Tag]

ABSTRACT: Impairment of oligodendrocyte (OL) myelinogenic potential, rather than inability of oligodendrocyte precursors to differentiate, is implicated in remyelination failure in demyelinating diseases such as multiple sclerosis. However, the mechanisms underlying myelinogenesis and age-related decline in remyelination remain elusive. Here, we identify a mature-OL-active transcriptional regulator Dor as a critical mediator of CNS myelination and remyelination. Genomic occupancy and transcriptomic analyses revealed that Dor interacts with Sox10 and targets the enhancers of myelinogenesis-regulatory genes including a newly identified OL-enriched nuclear factor Prr18 required for OL maturation. Metabolomic profiling showed that Dor is critical for alpha-ketoglutarate (alpha-KG) production and lipid biosynthesis. Supplementation with alpha-KG enhanced lipid biosynthesis and restored OL maturation defects in Dor-mutant mice while reversing the age-associated decline in remyelination efficiency and memory deficits in aging mice. Thus, our findings connect the OL-active Dor regulatory activity to alpha-KG-mediated lipid metabolism in mature OLs to thereby facilitate myelin production and remyelination.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE233591 | GEO | 2024/07/05

REPOSITORIES: GEO

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Dor regulates alpha-KG metabolic pathways in mature oligodendrocytes to enhance myelination and reverse age-related remyelination decline [RNA-seq]

Project description:Impairment of oligodendrocyte (OL) myelinogenic potential, rather than inability of oligodendrocyte precursors to differentiate, is implicated in remyelination failure in demyelinating diseases such as multiple sclerosis. However, the mechanisms underlying myelinogenesis and age-related decline in remyelination remain elusive. Here, we identify a mature-OL-active transcriptional regulator Dor as a critical mediator of CNS myelination and remyelination. Genomic occupancy and transcriptomic analyses revealed that Dor interacts with Sox10 and targets the enhancers of myelinogenesis-regulatory genes including a newly identified OL-enriched nuclear factor Prr18 required for OL maturation. Metabolomic profiling showed that Dor is critical for alpha-ketoglutarate (alpha-KG) production and lipid biosynthesis. Supplementation with alpha-KG enhanced lipid biosynthesis and restored OL maturation defects in Dor-mutant mice while reversing the age-associated decline in remyelination efficiency and memory deficits in aging mice. Thus, our findings connect the OL-active Dor regulatory activity to alpha-KG-mediated lipid metabolism in mature OLs to thereby facilitate myelin production and remyelination.

2024-07-05 | GSE233592 | GEO

Dor regulates alpha-KG metabolic pathways in mature oligodendrocytes to enhance myelination and reverse age-related remyelination decline [RNA-seq II]

2024-07-05 | GSE261859 | GEO

Respiratory infection with influenza A virus delays remyelination and alters oligodendrocyte metabolism.

Project description:Peripheral viral infection disrupts oligodendrocyte homeostasis such that endogenous remyelination may be affected. Here, we demonstrate that influenza A virus infection perpetuated a demyelination- and disease-associated oligodendrocyte (OL) phenotype following cuprizone-induced demyelination that resulted in delayed OL maturation and remyelination in the prefrontal cortex. Furthermore, we assessed cellular metabolism ex-vivo, and found that infection altered brain OL and microglia metabolism in a manner that opposed the metabolic profile induced by remyelination. Specifically, infection increased glycolytic capacity of OLs and microglia, an effect that was recapitulated by LPS stimulation of mixed glia cultures. In contrast, mitochondrial respiration was increased in OLs during remyelination, which was similarly observed in OLs of myelinating P14 mice compared to adult and aged mice. Collectively, our data indicate that respiratory viral infection is capable of suppressing remyelination, and suggest that metabolic dysfunction of OLs is implicated in remyelination impairment.

2024-08-14 | GSE253710 | GEO

Gsta4 restricts apoptosis in differentiating adult oligodendrocytes via Fas/Casp8/Bid-axis during homeostasis and remyelination

Project description:Arrest of oligodendrocyte (OL) differentiation and remyelination following myelin damage in Multiple Sclerosis (MS) are associated with disease progression but the underlying mechanism are elusive. We show that Glutathione S-transferase 4α (Gsta4) is highly expressed during adult OL differentiation and that its loss prevents differentiation into myelinating OLs. Also, Gsta4 appeared to be a novel target for Clemastine, in clinical trial for MS. Over-expression of Gsta4 reduced the expression of Fas and activity along the mitochondria-associated Casp8/Bid-axis in adult pre-OLs from the corpus callosum, together promoting enhanced pre-OL survival during differentiation. The Gsta4-mediated input on apoptosis during adult OL differentiation was further verified in the LPC and EAE model, where Casp8 were reduced in pre-OLs with high Gsta4 expression in an immune response-independent fashion. Our results place Gsta4 as a key regulator of intrinsic mechanisms beneficial for OL differentiation and remyelination, and as a possible target for future MS therapies.

2020-07-23 | GSE154922 | GEO

Transcription profiling of Arabidopsis dor mutant and wild type plants in response to drought stress.

Project description:ATH1 GeneChip was used for gene expression analysis of wild-type plants and dor mutant under drought treatment (both the wild-type and dor plants were grown under normal watering conditions for 24 days and then stressed by completely depriving of irrigation for 10 days). Two biological repeat experiments were conducted and the raw data was analyzed applying Affymetrix GCOS software. Experiment Overall Design: ATH1 GeneChip was used for gene expression analysis of wild-type plants and dor mutant under drought treatment (both the wild-type and dor plants were grown under normal watering conditions for 24 days and then stressed by completely depriving of irrigation for 10 days).

2008-10-26 | E-GEOD-10643 | biostudies-arrayexpress

Extrinsic and Intrinsic Regulation of DOR/TRP53INP2 Expression in Mice

Project description:The objective is to relate changes in expression of DOR/TRP53INP2, a factor involved in thyroid hormone action and autophagy, to body composition in mice fed a fat (FD) or high fat diet (HFD) for 8 days and in a genetically obese mouse model. We conclude that DOR expression depends on sex, fat content of diet, age, tissue type and tissue weight. 4 samples: 2 (normal diet control, fat diet) x2 replicates

2014-09-30 | E-GEOD-32872 | biostudies-arrayexpress

Small-molecule-induced epigenetic rejuvenation overcomes myelinogenic barriers and stimulates myelin repair [RNA-seq]

Project description:Failure of oligodendrocytes to remyelinate underlies diseases such as multiple sclerosis (MS). We found that epigenetic silencing prevents oligodendrocytes from producing myelin sheaths in demyelinating MS lesions. Here, we developed a transgenic reporter system to identify a small-molecule epigenetic modulator that stimulates oligodendrocyte maturation and myelin ensheathment in vitro. This compound promoted remyelination in animal models of MS and myelination of regenerated axons and increased myelin sheath lengths in human iPSC-derived organoids. Multi-omics analyses revealed that the compound induced an enhancer/super-enhancer landscape that upregulates crucial myelinogenesis-associated pathways, including RRAS2-AKT signaling, driving actin depolymerization necessary for myelin ensheathment. Strikingly, the compound also induced phase-separated nuclear condensates of SREBP1/2, which concentrate transcriptional co-activators to drive lipid and cholesterol biosynthesis. Silencing expression of a potential target of the small molecule, HDAC3, facilitated robust myelination and remyelination. Our findings suggest that small-molecule-modulated epigenome rejuvenation relieves epigenetic silencing barriers and promotes myelin repair.

2024-05-24 | GSE232955 | GEO

Small-molecule-induced epigenetic rejuvenation overcomes myelinogenic barriers and stimulates myelin repair [HiChIP]

2024-05-24 | GSE232954 | GEO

Small-molecule-induced epigenetic rejuvenation overcomes myelinogenic barriers and stimulates myelin repair [Cut&Run]

2024-05-24 | GSE232953 | GEO

Hikeshi-Mediated Nuclear Translocation of HSP70 Promotes Myelinogenesis by Preventing FBXW7-mediated Degradation of Sox10

Project description:Dysregulation of nucleocytoplasmic transport is intensively linked to many neurological diseases. Heat shock proteins 70 (HSP70s), which dramatically change its cellular localization upon stress, play important regulatory roles in nervous system. How the localization of HSP70s is regulated and the underlying physiological functions of this translocation are both poorly understood. Mutation in Hikeshi, encoding a nonconventional nuclear import carrier of HSP70s, lead to inherited leukodystrophy; however, the underlying mechanisms remain poorly understood. Here we showed that Hikeshi and HSP70s are essential for proper CNS myelination and remyelination. Loss of Hikeshi resulted in oligodendrocyte maturation arrest through preventing the nuclear translocation of HSP70s upon oligodendrocyte differentiation. HSP70s interacted with Sox10SOX10 in the nucleus and protected it from E3 ubiquitin ligase FBXW7-mediated ubiquitination degradation. Importantly, we discovered that the Hikeshi-dependent hyperthermia therapy, which induces nuclear import of HSP70s, promoted oligodendrocyte differentiation and remyelination following in vivo demyelinating injury. Overall, we demonstrate that Hikeshi-dependent nuclear translocation of HSP70s is essential for oligodendrocyte differentiation and myelinogenesis, and suggest the potential therapeutic value of hyperthermia therapy in myelin repair.

2023-02-19 | GSE225577 | GEO

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