Polycomb repression regulates Schwann cell proliferation and axon regeneration after nerve injury

H., Ki; Duong, Phu; Moran, John J.; Junaidi, Nabil; Svaren, John

doi:10.1002/glia.23500

Cited by 38 publications

(77 citation statements)

References 128 publications

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“…Several resources are available to identify SC-specific genes, including (1) expression profiles of peripheral nerve development and response to injury, [37][38][39][40][41][42][43][44] (2) profiling of sorted cell types in mouse embryonic skin, 30 and (3) RNA-seq profiling of >400 human tibial nerve samples, 45 along with many other tissues (Broad Institute; gtexportal.org). Several resources are available to identify SC-specific genes, including (1) expression profiles of peripheral nerve development and response to injury, [37][38][39][40][41][42][43][44] (2) profiling of sorted cell types in mouse embryonic skin, 30 and (3) RNA-seq profiling of >400 human tibial nerve samples, 45 along with many other tissues (Broad Institute; gtexportal.org).…”

Section: Rna-seq Analysis Of Human Skin Biopsiesmentioning

confidence: 99%

Schwann cell transcript biomarkers for hereditary neuropathy skin biopsies

Svaren

Moran

et al. 2019

Annals of Neurology

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Objective: Charcot-Marie-Tooth (CMT) disease is most commonly caused by duplication of a chromosomal segment surrounding Peripheral Myelin Protein 22, or PMP22 gene, which is classified as CMT1A. Several candidate therapies reduce Pmp22 mRNA levels in CMT1A rodent models, but development of biomarkers for clinical trials in CMT1A is a challenge given its slow progression and difficulty in obtaining nerve samples. Quantitative PCR measurements of PMP22 mRNA in dermal nerves were performed using skin biopsies in human clinical trials for CMT1A, but this approach did not show increased PMP22 mRNA in CMT1A patients compared to controls. One complicating factor is the variable amounts of Schwann cells (SCs) in skin. The objective of the study was to develop a novel method for precise evaluation of PMP22 levels in skin biopsies that can discriminate CMT1A patients from controls. Methods: We have developed methods to normalize PMP22 transcript levels to SC-specific genes that are not altered by CMT1A status. Several CMT1A-associated genes were assembled into a custom Nanostring panel to enable precise transcript measurements that can be normalized to variable SC content. Results: The digital expression data from Nanostring analysis showed reproducible elevation of PMP22 levels in CMT1A versus control skin biopsies, particularly after normalization to SC-specific genes. Interpretation: This platform should be useful in clinical trials for CMT1A as a biomarker of target engagement that can be used to optimize dosing, and the same normalization framework is applicable to other types of CMT.

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Section: Rna-seq Analysis Of Human Skin Biopsiesmentioning

confidence: 99%

Schwann cell transcript biomarkers for hereditary neuropathy skin biopsies

Svaren

Moran

et al. 2019

Annals of Neurology

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“…Nerve injury also induces epigenetic changes in Schwann cells that allows for reprogramming of these cells as they generate the cellular environment required for axon regeneration [105]. PRC2 has been shown to regulate the expression of Schwann cell repair genes and affect nerve injury response via H3K27me3.…”

Section: The Role Of Prc2 In Schwann Cell Development and Nerve Injurymentioning

confidence: 99%

“…PRC2 has been shown to regulate the expression of Schwann cell repair genes and affect nerve injury response via H3K27me3. In this context, PRC2 was found to repress nerve repair genes such as sonic hedgehog (Shh), glial-derived neurotrophic factors (Gdnf ), and brain-derived neurotrophic factors (Bdnf ) [105]. Nerve injury leads to reversal of PRC2 repression, H3K27 demethylation, and de-repression of these nerve repair genes [106].…”

Section: The Role Of Prc2 In Schwann Cell Development and Nerve Injurymentioning

confidence: 99%

“…Nerve injury leads to reversal of PRC2 repression, H3K27 demethylation, and de-repression of these nerve repair genes [106]. Loss of PRC2 repression in an Eed conditional knockout mouse model was sufficient to activate these repair genes in uninjured nerves; however, there was no evidence of accelerated nerve injury repair [105]. It is possible that the linkages demonstrating the relationship between nerve injury and PRC2 may yield important clues into the pathogenesis of disease progression of benign neurofibromas to MPNSTs.…”

Section: The Role Of Prc2 In Schwann Cell Development and Nerve Injurymentioning

confidence: 99%

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The Role of Polycomb Repressive Complex in Malignant Peripheral Nerve Sheath Tumor

Zhang

Murray

et al. 2020

Genes

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Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft tissue sarcomas that can arise most frequently in patients with neurofibromatosis type 1 (NF1). Despite an increasing understanding of the molecular mechanisms that underlie these tumors, there remains limited therapeutic options for this aggressive disease. One potentially critical finding is that a significant proportion of MPNSTs exhibit recurrent mutations in the genes EED or SUZ12, which are key components of the polycomb repressive complex 2 (PRC2). Tumors harboring these genetic lesions lose the marker of transcriptional repression, trimethylation of lysine residue 27 on histone H3 (H3K27me3) and have dysregulated oncogenic signaling. Given the recurrence of PRC2 alterations, intensive research efforts are now underway with a focus on detailing the epigenetic and transcriptomic consequences of PRC2 loss as well as development of novel therapeutic strategies for targeting these lesions. In this review article, we will summarize the recent findings of PRC2 in MPNST tumorigenesis, including highlighting the functions of PRC2 in normal Schwann cell development and nerve injury repair, as well as provide commentary on the potential therapeutic vulnerabilities of a PRC2 deficient tumor cell.

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“…A sequential response triggered after peripheral nerve injury (PNI) is known as Wallerian degeneration (Jang et al, ). Subsequently, Schwann cells remove axonal and myelin debris, and secrete cytokines, thereby accelerating axonal regeneration (Ma, Duong, Moran, Junaidi, & Svaren, ; Stierli et al, ). In addition, the peripheral nerve microenvironment contains a variety of neurotrophic factors or growth factors, which play an irreplaceable role in nerve regeneration.…”

Section: Introductionmentioning

confidence: 99%

Signatures of altered DNA methylation gene expression after central and peripheral nerve injury

Shi

Zhou

Wang

et al. 2019

Journal Cellular Physiology

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Nerve damage can lead to movement and sensory dysfunction, with high morbidity and disability rates causing severe burdens on patients, families, and society. DNA methylation is a kind of epigenetics, and a great number of previous studies have demonstrated that DNA methylation plays an important role in the process of nerve regeneration and remodeling. However, compared with the central nervous system, the peripheral nervous system shows stronger recovery after injury, which is related to the complex microenvironment and epigenetic changes occurring at the site of injury. Therefore, what common epigenetic changes between the central and peripheral nervous systems remain to be elucidated. We first screened differential methylation genes after spinal cord injury and sciatic nerve injury using whole‐genome bisulfite sequencing and methylated DNA immunoprecipitation sequencing, respectively. Subsequently, a total of 16 genes had the same epigenetic changes after spinal cord injury and sciatic nerve injury. The Gene Ontology analysis and Kyoto Encyclopedia of Genes and Genomes enrichment analysis were performed to identify the critical biological processes and pathways. Furthermore, a protein−protein interaction network analysis indicated that Dnm3, Ntrk3, Smurf1, Dpysl2, Kalrn, Shank1, Dlg2, Arsb, Reln, Bmp5, Numbl, Prickle2, Map6, and Htr7 were the core genes. These outcomes may provide novel insights into the molecular mechanism of the subacute phase of nerve injury. These verified genes can offer potential diagnostic and therapeutic targets for nerve injury.

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Polycomb repression regulates Schwann cell proliferation and axon regeneration after nerve injury

Cited by 38 publications

References 128 publications

Schwann cell transcript biomarkers for hereditary neuropathy skin biopsies

Schwann cell transcript biomarkers for hereditary neuropathy skin biopsies

The Role of Polycomb Repressive Complex in Malignant Peripheral Nerve Sheath Tumor

Signatures of altered DNA methylation gene expression after central and peripheral nerve injury

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