Alteration in global DNA methylation status following preconditioning injury influences axon growth competence of the sensory neurons

Shin, Hae Young; Kim, Kyung; Kwon, Min Jung; Oh, Young Joo; Kim, Eun Hye; Kim, Hyung Soon; Hong, Chang Pyo; Lee, Jae Hyung; Lee, KiYoung; Kim, Byung Gon

doi:10.1016/j.expneurol.2020.113177

Cited by 10 publications

(14 citation statements)

References 56 publications

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“…The symbols preceding the gene titles are matched with those designated in the volcano plots (C,D). using a customized panel of genes consisting of 44 RAGs that were selected based on more than several previous gene expression studies in DRGs (Shin et al, 2020). As expected, the conditional deletion of Myc led to a marked decrease in Myc gene expression in DRGs from sham-operated animals (Fig.…”

Section: Myc Is Necessary For the Enhancement Of Regenerative Capacity And Injury-induced Upregulation Of A Group Of Ragsmentioning

confidence: 73%

“…In our previous study to examine a potential role of DNA methylation in the orchestrated transcription of RAGs in the preconditioning injury model (Shin et al, 2020), we profiled the DNA methylome using methylated DNA immunoprecipitation sequencing (MeDIP-seq) in DRGs following SNI and found that the changes in DNA methylation were not significantly correlated with the transcription levels of the RAGs. As a next approach, we sought to examine whether upstream transcription TF genes that can bind to the RAG promoters are affected by DNA methylation.…”

Section: Identification Of Myc As An Upstream Tf Gene For Ragsmentioning

confidence: 99%

“…As a next approach, we sought to examine whether upstream transcription TF genes that can bind to the RAG promoters are affected by DNA methylation. We curated 81 RAGs based on the literature review that were consistently reported to increase in DRGs following preconditioning SNI (Shin et al, 2020), and then listed TF genes that are known to interact with the curated RAGs based on the Open Regulatory Annotation (ORegAnno) database (Griffith et al, 2008). We selected TF genes of which methylation level was changed by more than twofold and the expression level was increased following SNI (Table 1).…”

Section: Identification Of Myc As An Upstream Tf Gene For Ragsmentioning

confidence: 99%

“…Epigenetic mechanisms also play a crucial role in the transcriptional activation of RAGs in the preconditioning model (Cho et al, 2013;Puttagunta et al, 2014;Weng et al, 2017). Our previous study examined changes in DNA methylome in the preconditioning injury model and found that global DNA methylation does not correlate with injury-induced RAG upregulation (Shin et al, 2020). We reasoned that DNA methylation might be involved in the activation of upstream TF genes that in turn regulate transcription of many RAGs as a gene expression hub.…”

Section: Introductionmentioning

confidence: 96%

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Role ofMycProto-Oncogene as a Transcriptional Hub to Regulate the Expression of Regeneration-Associated Genes following Preconditioning Peripheral Nerve Injury

et al. 2020

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Preconditioning peripheral nerve injury enhances the intrinsic growth capacity of DRGs sensory axons by inducing transcriptional upregulation of the regeneration-associated genes (RAGs). However, it is still unclear how preconditioning injury leads to the orchestrated induction of many RAGs. The present study identified Myc proto-oncogene as a transcriptional hub gene to regulate the expression of a distinct subset of RAGs in DRGs following the preconditioning injury. We demonstrated that c-MYC bound to the promoters of certain RAGs, such as Jun, Atf3, and Sprr1a, and that Myc upregulation following SNI preceded that of the RAGs bound by c-MYC. Marked DNA methylation of the Myc exon 3 sequences was implicated in the early transcriptional activation and accompanied by open histone marks. Myc deletion led to a decrease in the injury-induced expression of a distinct subset of RAGs, which were highly overlapped with the list of RAGs that were upregulated by Myc overexpression. Following dorsal hemisection spinal cord injury in female rats, Myc overexpression in DRGs significantly prevented the retraction of the sensory axons in a manner dependent on its downstream RAG, June. Our results suggest that Myc plays a critical role in axon regeneration via its transcriptional activity to regulate the expression of a spectrum of downstream RAGs and subsequent effector molecules. Identification of more upstream hub transcription factors and the epigenetic mechanisms specific for individual hub transcription factors would advance our understanding of how the preconditioning injury induces orchestrated upregulation of RAGs.

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Section: Myc Is Necessary For the Enhancement Of Regenerative Capacity And Injury-induced Upregulation Of A Group Of Ragsmentioning

confidence: 73%

Section: Identification Of Myc As An Upstream Tf Gene For Ragsmentioning

confidence: 99%

Section: Identification Of Myc As An Upstream Tf Gene For Ragsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 96%

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Role ofMycProto-Oncogene as a Transcriptional Hub to Regulate the Expression of Regeneration-Associated Genes following Preconditioning Peripheral Nerve Injury

et al. 2020

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“…After SNC, the intrinsic growth state of DRG neurons increases, and the preinjured neurons elicit a robust regenerative response to a second lesion of either the peripheral or the central axon (McQuarrie & Grafstein, 1973; McQuarrie et al., 1978). This “conditioning” effect can be observed both in vivo and in culture (Hur et al., 2013; Shin et al., 2020; Smith & Skene, 1997). We performed SNC, and DRG neurons from the injured mice were isolated at 3 days after injury for primary culture.…”

Section: Resultsmentioning

confidence: 98%

Comparing axon regeneration in male and female mice after peripheral nerve injury

Jang

Bae

Yang

et al. 2021

J of Neuroscience Research

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Axons in the adult mammalian central nervous system fail to regenerate after injury. By contrast, spontaneous axon regeneration occurs in the peripheral nervous system (PNS) due to a supportive PNS environment and an increase in the intrinsic growth potential induced by injury via cooperative activation of multifaceted biological pathways. This study compared axon regeneration and injury responses in C57BL/6 male and female mice after sciatic nerve crush (SNC) injury. The extent of axon regeneration in vivo was indistinguishable in male and female mice when observed at 3 days after SNC injury, and primary dorsal root ganglion (DRG) neurons from injured, male and female mice extended axons to a similar length. Moreover, the induction of selected regeneration‐associated genes (RAGs), such as Atf3, Sprr1a, Gap43, Sox11, Jun, Gadd45a, and Smad1 were comparable in male and female DRGs when assessed by quantitative real‐time reverse transcription polymerase chain reaction. Furthermore, the RNA‐seq analysis of male and female DRGs revealed that differentially expressed genes (DEGs) in SNC groups compared to sham‐operated groups included many common genes associated with neurite outgrowth. However, we also found that a large number of genes in the DEGs were sex dependent, implicating the involvement of distinct gene regulatory network in the two sexes following peripheral nerve injury. In conclusion, we found that male and female mice mounted a comparable axon regeneration response and many RAGs were commonly induced in response to SNC. However, given that many DEGs were sex‐dependently expressed, future studies are needed to investigate whether they contribute to peripheral axon regeneration, and if so, to what extent.

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Nanogel-mediated therapeutic delivery across blood-cerebrospinal fluid and blood-spinal cord barriers

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Alteration in global DNA methylation status following preconditioning injury influences axon growth competence of the sensory neurons

Cited by 10 publications

References 56 publications

Role ofMycProto-Oncogene as a Transcriptional Hub to Regulate the Expression of Regeneration-Associated Genes following Preconditioning Peripheral Nerve Injury

Role ofMycProto-Oncogene as a Transcriptional Hub to Regulate the Expression of Regeneration-Associated Genes following Preconditioning Peripheral Nerve Injury

Comparing axon regeneration in male and female mice after peripheral nerve injury

Nanogel-mediated therapeutic delivery across blood-cerebrospinal fluid and blood-spinal cord barriers

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