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Cdk7 regulates peripheral myelin sheath extension and lipid content.

ABSTRACT: Myelin allows saltatory transmission of action potentials along axons and functionally relies on its unique constitution. Schwann cells (SC) are the glial cells responsible for myelination in the peripheral nervous system (PNS), and their differentiation constitutes a stepwise process involving accurate coordination of proliferation and fine-tuned gene expression.We previously reported that Cdk7, a regulator of cell cycle progression and transcription, regulates myelin gene expression in oligodendrocytes and contributes to myelin maintenance in the adult central nervous system. Using conditional Cdk7 knock-out mice, we provide evidence that Cdk7 is not required for myelin initiation but is needed for the correct rate of myelination of larger calibre fibres, as well as for myelin elongation and rapid nerve conduction. We show that Cdk7 loss results in significant dysregulation of lipid-related genes in SCs in addition to a reduction in myelin protein zero, leading to disturbed myelin stoichiometry. Finally, we show that Rxrγ, a nuclear receptor involved in lipid metabolism, is downregulated in the absence of Cdk7 and that Cdk7 is required for the myelination-promoting effect of Rxrγ in myelinating dorsal root ganglion explants.

ORGANISM(S): Mus musculus

PROVIDER: GSE308035 | GEO | 2026/07/29

REPOSITORIES: GEO

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Project description:DNA methylation is a key epigenetic regulator of mammalian embryogenesis and somatic cell differentiation. Using high-resolution genome-scale maps of methylation patterns, we show that the formation of myelin in the peripheral nervous system, proceeds with progressive DNA demethylation, which coincides with an upregulation of critical genes of the myelination process. More importantly, we found that, in addition to expression of DNA methyltransferases and demethylases, the levels of S-adenosylmethionine (SAMe), the principal biological methyl donor, could also play a critical role in regulating DNA methylation during myelination and in the pathogenesis of diabetic neuropathy. In summary, this study provides compelling evidence that SAMe levels need to be tightly controlled to prevent aberrant DNA methylation patterns, and together with recently published studies on the influence of SAMe on histone methylation in cancer and embryonic stem cell differentiation show that in diverse biological processes, the methylome, and consequently gene expression patterns, are critically dependent on levels of SAMe. Axonal myelination by Schwann cells in the peripheral nervous system is essential for rapid saltatory impulse conduction, and malformation or destruction of myelin sheaths can lead to severe motor and sensory disabilities (peripheral neuropathies). Using high-resolution genome-scale methylome maps, we found that DNA methylation could play a critical role in the generation of myelinated Schwann cells. This process was accompanied by a global DNA demethylation at most genomic elements. Notably, demethylation at gene-regulatory regions was associated with activation of critical myelination-specific genes. Furthermore, we found an aberrant DNA methylation pattern in a mouse model of diabetic neuropathy, which could be involved in the pathogenesis of the disease. Importantly, we found that these methylation patterns in both situations could be regulated by levels of S-adenosylmethionine (SAMe), the principal biological methyl donor. Together with recent studies on the influence of SAMe on histone methylation in diverse biological processes, we conclude that the methylation landscape of cells could be critically dependent on levels of SAMe. These provide a mechanistic link between metabolism and gene regulatory networks in normal and pathological situations. Sciatic nerves from post natal day 90 GNMT (wt and KO) mice of either sex were dissected and pooled together, 2 replicates per sample group.

Project description:DNA methylation is a key epigenetic regulator of mammalian embryogenesis and somatic cell differentiation. Using high-resolution genome-scale maps of methylation patterns, we show that the formation of myelin in the peripheral nervous system, proceeds with progressive DNA demethylation, which coincides with an upregulation of critical genes of the myelination process. More importantly, we found that, in addition to expression of DNA methyltransferases and demethylases, the levels of S-adenosylmethionine (SAMe), the principal biological methyl donor, could also play a critical role in regulating DNA methylation during myelination and in the pathogenesis of diabetic neuropathy. In summary, this study provides compelling evidence that SAMe levels need to be tightly controlled to prevent aberrant DNA methylation patterns, and together with recently published studies on the influence of SAMe on histone methylation in cancer and embryonic stem cell differentiation show that in diverse biological processes, the methylome, and consequently gene expression patterns, are critically dependent on levels of SAMe. Axonal myelination by Schwann cells in the peripheral nervous system is essential for rapid saltatory impulse conduction, and malformation or destruction of myelin sheaths can lead to severe motor and sensory disabilities (peripheral neuropathies). Using high-resolution genome-scale methylome maps, we found that DNA methylation could play a critical role in the generation of myelinated Schwann cells. This process was accompanied by a global DNA demethylation at most genomic elements. Notably, demethylation at gene-regulatory regions was associated with activation of critical myelination-specific genes. Furthermore, we found an aberrant DNA methylation pattern in a mouse model of diabetic neuropathy, which could be involved in the pathogenesis of the disease. Importantly, we found that these methylation patterns in both situations could be regulated by levels of S-adenosylmethionine (SAMe), the principal biological methyl donor. Together with recent studies on the influence of SAMe on histone methylation in diverse biological processes, we conclude that the methylation landscape of cells could be critically dependent on levels of SAMe. These provide a mechanistic link between metabolism and gene regulatory networks in normal and pathological situations. Sciatic nerves from C57Bl6J mice of either sex, were dissected and pooled together at different developmental stages, 3 replicates per sample group.

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Cdk7 regulates peripheral myelin sheath extension and lipid content.

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