Enhanced neuronal regeneration in the CAST/Ei mouse strain is linked to expression of differentiation markers after injury

Lisi, Véronique; Singh, Bhagat; Giroux, Michel; Guzman, Elmer; Painter, Michio W.; Cheng, Yuyu; Huebner, Eric A.; Coppola, Giovanni; Costigan, Michael; Woolf, Clifford J.; Kosik, Kenneth S.

doi:10.1101/160366

Cited by 10 publications

(13 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…DRG gene regulation plays pivotal roles in neuropathic pain genesis [30][31][32] , and RNA sequencing studies have elucidated the molecular signature underlying neuropathic pain induced by nerve injury [33][34][35][36][37][38][39][40] . We compared our CIPN induced DRG DEGs with results from nerve injury induced neuropathic pain 38,41 .…”

Section: Resultsmentioning

confidence: 99%

Circadian regulation of chemotherapy-induced peripheral neuropathic pain and the underlying transcriptomic landscape

Kim

Lee

Koike

et al. 2020

Sci Rep

View full text Add to dashboard Cite

Growing evidence demonstrates circadian rhythms of pain hypersensitivity in various chronic disorders. In chemotherapy-induced peripheral neuropathy (CIPN), agents such as paclitaxel are known to elicit chronic neuropathic pain in cancer patients and seriously compromise their quality of life. Here, we report that the mechanical threshold for allodynia in paclitaxel-treated rats exhibited a robust circadian oscillation, reaching the nadir during the daytime (inactive phase). Using Per2::LucSV circadian reporter mice expressing a PER2::LUC fusion protein, we isolated dorsal root ganglia (DRG), the primary sensory cell body for peripheral nerve injury generated hypersensitivity, and monitored ex vivo reporter bioluminescence. We observed strong circadian reporter rhythms in DRG neurons which are highly entrainable by external cues. Paclitaxel treatment significantly lengthened DRG circadian periods, with little effects on the amplitude of oscillation. We further observed the core protein BMAL1 and PER2 in DRG neurons and satellite cells. Using DRG and dorsal horn (DH; another key structure for CIPN pain response) tissues from vehicle and paclitaxel treated rats, we performed RNA-sequencing and identified diurnal expression of core clock genes as well as clock-controlled genes in both sites. Interestingly, 20.1% and 30.4% of diurnal differentially expressed genes (DEGs) overlapped with paclitaxel-induced DEGs in the DRG and the DH respectively. In contrast, paclitaxelinduced DEGs displayed only a modest overlap between daytime and nighttime (Zeitgeber Time 8 and 20). Furthermore, paclitaxel treatment induced de novo diurnal DEGs, suggesting reciprocal interaction of circadian rhythms and chemotherapy. Our study therefore demonstrates a circadian oscillation of CIPN and its underlying transcriptomic landscape. Numerous vital processes in our body display time-of-day dependent oscillation. Such daily rhythms of tissuespecific and systemic functions are driven by the endogenous circadian clock where cellular oscillators, containing interlocked transcriptional-translational loops composed of positive (CLOCK/NPAS2, BMAL1, RORs) and negative (PERIOD1/2 (PER1/2) and CRYPTOCHROME1/2 (CRY1/2

show abstract

Section: Resultsmentioning

confidence: 99%

Circadian regulation of chemotherapy-induced peripheral neuropathic pain and the underlying transcriptomic landscape

Kim

Lee

Koike

et al. 2020

Sci Rep

View full text Add to dashboard Cite

show abstract

“…injured (5 d after SNI) conditions (57). Heatmaps revealed two clusters with an opposite trend (Fig.…”

Section: Dna Methylation Is Required For Axon Regenerationmentioning

confidence: 94%

“…55 and from validated targets from MetaCore. RNA-seq data from naïve DRG and DRG 5 d after sciatic nerve crush obtained from CAST/Ei mouse (57) were downloaded from Gene Expression Omnibus (GSE67130). RNA-seq data from E12.5 and E17.5 DRG neurons (56) were downloaded from Gene Expression Omnibus (GSE66128).…”

Section: Methodsmentioning

confidence: 99%

Epigenetic regulator UHRF1 inactivates REST and growth suppressor gene expression via DNA methylation to promote axon regeneration

Mahar

Ewan

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Injured peripheral sensory neurons switch to a regenerative state after axon injury, which requires transcriptional and epigenetic changes. However, the roles and mechanisms of gene inactivation after injury are poorly understood. Here, we show that DNA methylation, which generally leads to gene silencing, is required for robust axon regeneration after peripheral nerve lesion. Ubiquitin-like containing PHD ring finger 1 (UHRF1), a critical epigenetic regulator involved in DNA methylation, increases upon axon injury and is required for robust axon regeneration. The increased level of UHRF1 results from a decrease in miR-9. The level of another target of miR-9, the transcriptional regulator RE1 silencing transcription factor (REST), transiently increases after injury and is required for axon regeneration. Mechanistically, UHRF1 interacts with DNA methyltransferases (DNMTs) and H3K9me3 at the promoter region to repress the expression of the tumor suppressor gene phosphatase and tensin homolog (PTEN) and REST. Our study reveals an epigenetic mechanism that silences tumor suppressor genes and restricts REST expression in time after injury to promote axon regeneration.

show abstract

“…The genes related to the Notch signaling pathway are highlighted by red circles. B: Expression of Notch signaling components in DRG neurons of pure C57BL/6 and CAST/Ei mice, using data from Lisi, Veronique, et al (7). Notch signaling pathway components were upregulated by injury in DRG neurons.…”

Section: Allelic Expression and Methylation Analysismentioning

confidence: 99%

“…One of the major epigenetic regulators, DNA methylation, is associated with changes in transcriptional programs in response to intrinsic and extrinsic signals. Previous genomic studies examined the relationship between DNA methylation and transcriptional change in sensory neurons via transcriptome and methylome profiling in whole dorsal root ganglia (DRG) (5)(6)(7)(8). However, these results are confounded by the contamination of non-neuronal cells as well as the 5 heterogeneity of subtypes of DRG neurons.…”

Section: Introductionmentioning

confidence: 99%

Single cell multi-omics analysis reveals novel roles for DNA methylation in sensory neuron injury responses

Fan

2019

Preprint

View full text Add to dashboard Cite

DNA methylation is implicated in neuronal injury response and regeneration, but its role in regulating stable transcription changes in different types of dorsal root ganglion (DRG) neurons is unclear. In this study, we simultaneously profiled both the DNA methylome and mRNA transcriptome from single DRG neurons at different ages under either control or 20 peripheral nerve injury condition. We found that age-related expression changes in Notch signaling genes and methylation changes at Notch receptor binding sites are associated with the age-dependent decline in peripheral nerve regeneration potential. Moreover, selective hypomethylation of AP-1 complex binding sites on regeneration-associated gene (RAG) promoters coincides with RAG transcriptional upregulation after injury. Consistent with the 25 findings that different subtypes of DRG neurons exhibit distinct methylome changes upon injury responses, in a hybrid CAST/Ei; C57BL/6 genetic background, we further observed allelespecific gene regulation and methylation changes for many RAGs after injury. We suggest that the genetic background determines distinct allele-specific DNA methylomes, which contribute to age-dependent regulation and neuronal subtype-specific injury-responses in different mouse 30 strains. Introduction:

show abstract

Enhanced neuronal regeneration in the CAST/Ei mouse strain is linked to expression of differentiation markers after injury

Cited by 10 publications

References 45 publications

Circadian regulation of chemotherapy-induced peripheral neuropathic pain and the underlying transcriptomic landscape

Circadian regulation of chemotherapy-induced peripheral neuropathic pain and the underlying transcriptomic landscape

Epigenetic regulator UHRF1 inactivates REST and growth suppressor gene expression via DNA methylation to promote axon regeneration

Single cell multi-omics analysis reveals novel roles for DNA methylation in sensory neuron injury responses

Contact Info

Product

Resources

About