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MiRNA-9 regulates axon regeneration through the transcriptional regulator REST and the epigenetic factor UHRF1 [miRNA array]

ABSTRACT: Injured sensory neurons successfully activate a pro-regenerative transcriptional program to enable axon regeneration and functional recovery, but the roles of genes that are inactivated after injury remain poorly understood. Analysis of the miRNA expression profile triggered by axon injury revealed down-regulation of the neural development associated miRNA, miR-9. A target of miR-9 is the critical epigenetic regulator involved in DNA methylation, ubiquitin-like containing PHD ring finger 1 (UHRF1), which increased after injury to promote axon regeneration. UHRF1 is known to repress the transcription of tumor suppressor genes through DNA methylation and we show that UHRF1 interacts with DNMT1 to methylate the promoter region of the tumor suppressors PTEN and CDKN1A, thereby triggering their inactivation. We also reveal that UHRF1 represses the transcriptional regulator REST. Our findings define an epigenetic mechanism that silences the transcription of axon growth suppressors to promote axon regeneration in sensory neurons.

ORGANISM(S): Mus musculus synthetic construct

PROVIDER: GSE90475 | GEO | 2021/12/01

REPOSITORIES: GEO

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miRNA-9 regulates axon regeneration through the transcriptional regulator REST and the epigenetic factor UHRF1 [RNA-seq]

Project description:Injured sensory neurons successfully activate a pro-regenerative transcriptional program to enable axon regeneration and functional recovery, but the roles of genes that are inactivated after injury remain poorly understood. Analysis of the miRNA expression profile triggered by axon injury revealed down-regulation of the neural development associated miRNA, miR-9. A target of miR-9 is the critical epigenetic regulator involved in DNA methylation, ubiquitin-like containing PHD ring finger 1 (UHRF1), which increased after injury to promote axon regeneration. UHRF1 is known to repress the transcription of tumor suppressor genes through DNA methylation and we show that UHRF1 interacts with DNMT1 to methylate the promoter region of the tumor suppressors PTEN and CDKN1A, thereby triggering their inactivation. We also reveal that UHRF1 represses the transcriptional regulator REST. Our findings define an epigenetic mechanism that silences the transcription of axon growth suppressors to promote axon regeneration in sensory neurons.

2021-12-01 | GSE90476 | GEO

Self-renewing macrophages in dorsal root ganglia contribute to promote nerve regeneration

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2023-02-07 | GSE190283 | GEO

Activating injury-responsive genes with hypoxia enhances axon regeneration through neuronal HIF-1α

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2016-01-21 | GSE73415 | GEO

RNA-sequencing of injured cultured dorsal root ganglion neurons over time

Project description:Injured sensory neurons activate a transcriptional program necessary for robust axon regeneration and eventual target reinnervation. Understanding the transcriptional regulators that govern this axon regenerative response may guide therapeutic strategies to promote axon regeneration in the injured nervous system. Here, we used cultured dorsal root ganglia neurons to identify pro-regenerative transcription factors. Using RNA sequencing, we first characterized this neuronal culture and determined that embryonic day 13.5 DRG (eDRG) neurons cultured for 7 days are similar to e15.5 DRG neurons in vivo and that all neuronal subtypes are represented. This eDRG neuronal culture does not contain other non-neuronal cell types. Next, we performed RNA sequencing at different time points after in vitro axotomy. Analysis of differentially expressed genes revealed upregulation of know regeneration associated transcription factors, including Jun Atf3 and Rest, paralleling the axon injury response in vivo. Analysis of transcription factor binding sites in differentially expressed genes revealed other known transcription factors promoting axon regeneration, such as Myc, Hif1a, Pparg, Ascl1a, Srf, as well as other transcription factors not yet characterized in axon regeneration. We next tested if overexpression of known and novel candidate transcription factors alone or in combination promote axon regeneration in vitro. Our results demonstrate that expression of Ctcf with Yy1 or E2f2 enhances in vitro axon regeneration. Our analysis reveals that pairs of transcription factors can functionally synergize to promote axon regeneration and highlight that transcription factor interaction play an important role as a regulator of axon regeneration.

2022-06-20 | GSE138480 | GEO

Immunity to the microbiota promotes sensory neurons regeneration via IL-17A

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2023-02-07 | GSE196994 | GEO

scRNAseq analysis of mouse L4 whole dorsal root ganglions with and without sciatic nerve crush injury

Project description:Peripheral sensory neurons with cell body in dorsal root ganglia (DRG) switch to a regenerative state after nerve injury to enable axon regeneration and functional recovery. Studies of nerve injury responses in sensory neurons have revealed signaling and transcriptional mechanisms that increase their intrinsic regenerative capacity. However, the extent to which satellite glial cells (SGC), which completely surround the neuronal soma contribute to these responses remains unexplored. Using single cell RNA-seq, we defined the transcriptional profile of SGC in naïve and injured conditions and identified Fabp7, also known as BLBP, as a novel marker of SGC. We report that nerve injury elicits gene expression changes in SGC, which are mostly related to lipid metabolism, specifically fatty acid synthesis and the peroxisome proliferator-activated receptor (PPAR) signaling. Conditional deletion of Fatty acid synthase (Fasn), the key enzyme in de novo fatty acid synthesis, specifically in SGC, impairs axon regeneration. Treatment with fenofibrate, a PPARa agonist, rescues the impaired regeneration, suggesting that PPRAa, which belongs to a family of lipid regulated transcription factors, functions downstream of fatty acid synthesis in SGC to promote axon regeneration. These results unravel fatty acid synthesis in SGC as a fundamental novel mechanism mediating axon regeneration in mature peripheral nerves.

2020-08-23 | GSE139103 | GEO

Sensory neurons display cell-type specific vulnerability to loss of neuron-glia interactions

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2022-06-11 | GSE205561 | GEO

Sc-RNA seq for intrinsic mechanisms of distinct axonal growth capacity in different peripheral sensory neuron subtypes

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Signaling to Transcription Networks in the Neuronal Retrograde Injury Response

Project description:Retrograde signaling from axon to soma activates intrinsic regeneration mechanisms in lesioned peripheral sensory neurons; however, the links between axonal injury signaling and the cell body response are not well understood. Here, we used phosphoproteomics and microarrays to implicate ~900 phosphoproteins in retrograde injury signaling in rat sciatic nerve axons in vivo and ~4500 transcripts in the in vivo response to injury in the dorsal root ganglia. Computational analyses of these data sets identified ~400 redundant axonal signaling networks connected to 39 transcription factors implicated in the sensory neuron response to axonal injury. Experimental perturbation of individual overrepresented signaling hub proteins, including Abl, AKT, p38, and protein kinase C, affected neurite outgrowth in sensory neurons. Paradoxically, however, combined perturbation of Abl together with other hub proteins had a reduced effect relative to perturbation of individual proteins. Our data indicate that nerve injury responses are controlled by multiple regulatory components, and suggest that network redundancies provide robustness to the injury response Microarrays were run on mRNA extracted from adult rat L4 and L5 DRGs cells after 1,3,8,12,16,18,24, and 28 hours after a sciatic nerve (proximal and distal) lesion.

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