Dynamic Regulation of Schwann Cell Enhancers after Peripheral Nerve Injury

Hung, Holly A.; Sun, Guannan; Keleş, Sündüz; Svaren, John

doi:10.1074/jbc.m114.622878

Cited by 107 publications

(130 citation statements)

References 94 publications

(145 reference statements)

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“…Such low levels of derepression may not be sufficient to alter Schwann cell fate or the myelination program. Ezh2-suppressed Schwann cells in culture showed a marked decrease in myelin gene expression accompanied with a significant increase of negative regulators p57 and Hes5 (Heinen et al, 2012). We also observed a moderate decrease of several myelin genes (Fig.…”

Section: Discussionsupporting

confidence: 53%

“…In addition, recent studies demonstrated that dysregulation of the ␣6␤4 integrin signaling that drives phosphorylation of NDRG1 results in hypermyelination and myelin folding (Nodari et al, 2008;Heller et al, 2014). However, we found no significant changes in either NDRG1 phosphorylation (data not shown) or phosphorylation of focal adhesion kinase, a ubiquitously expressed cytoskeletal scaffolding protein involved in cytoskeletal regulation and myelination (Grove and Brophy, 2014).…”

Section: Discussioncontrasting

confidence: 53%

“…H3K27me3 is established at 15 of the 32 genes in neural crest cells, including many of the neuronal differentiation genes, suggesting that the derepression of neuronal genes in the Eed cKO nerves reflects a reversal of H3K27me3-mediated repression established early in the Schwann cell lineage. In contrast, Emb, Foxs1, and Igf2bp1 are expressed in neural crest and become repressed during Schwann cell development (Buchstaller et al, 2004;Heglind et al, 2005). Accordingly, ChIP-seq data of neural crest cells show the absence of H3K27me3 at these genes and our data indicate repression of such genes is at least partially dependent on the action of EED in the PRC2 complex.…”

Section: Genome-wide Identification Of H3k27me3-bound Genesmentioning

confidence: 67%

“…Changes in nmSC morphology would presumably impair axon protection as indicated by retracted nmSC processes that are free from axons and a decreased number of unmyelinated axons. Interestingly, a previous study using shRNA-mediated suppression of Ezh2 in Schwann cells in culture showed shortening of cellular processes (Heinen et al, 2012), and we speculate that the Remak bundle disruption may be due to a similar phenomenon. Our data indicate a crucial function of the PRC2-mediated maintenance of peripheral nerves, given that removal of the EED subunit results in progressive hypermyelination and abnormalities affecting both myelinated fibers and Remak bundles.…”

Section: Discussionmentioning

confidence: 99%

“…The raw data files are deposited in National Center for Biotechnology Information Gene Expression Omnibus under accession number GSE64260. Hypergeometric optimization of motif enrichment (HOMER;Heinz et al, 2010) was used to determine enriched binding regions for H3K27me3-ChIP relative to sequencing of an input chromatin sample. Peaks called with HOMER used a minimum peak cutoff score of 25.…”

Section: Methodsmentioning

confidence: 99%

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Regulation of Peripheral Nerve Myelin Maintenance by Gene Repression through Polycomb Repressive Complex 2

Hung

Srinivasan

et al. 2015

J. Neurosci.

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Myelination of peripheral nerves by Schwann cells requires coordinate regulation of gene repression as well as gene activation. Several chromatin remodeling pathways critical for peripheral nerve myelination have been identified, but the functions of histone methylation in the peripheral nerve have not been elucidated. To determine the role of histone H3 Lys27 methylation, we have generated mice with a Schwann cell-specific knock-out of Eed, which is an essential subunit of the polycomb repressive complex 2 (PRC2) that catalyzes methylation of histone H3 Lys27. Analysis of this mutant revealed no significant effects on early postnatal development of myelin. However, its loss eventually causes progressive hypermyelination of small-diameter axons and apparent fragmentation of Remak bundles. These data identify the PRC2 complex as an epigenomic modulator of mature myelin thickness, which is associated with changes in Akt phosphorylation. Interestingly, we found that Eed inactivation causes derepression of several genes, e.g., Sonic hedgehog (Shh) and Insulin-like growth factor-binding protein 2 (Igfbp2), that become activated after nerve injury, but without activation of a primary regulator of the injury program, c-Jun. Analysis of the activated genes in cultured Schwann cells showed that Igfbp2 regulates Akt activation. Our results identify an epigenomic pathway required for establishing thickness of mature myelin and repressing genes that respond to nerve injury.

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Section: Discussionsupporting

confidence: 53%

Section: Discussioncontrasting

confidence: 53%

Section: Genome-wide Identification Of H3k27me3-bound Genesmentioning

confidence: 67%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Regulation of Peripheral Nerve Myelin Maintenance by Gene Repression through Polycomb Repressive Complex 2

Hung

Srinivasan

et al. 2015

J. Neurosci.

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Variation in SIPA1L2 is correlated with phenotype modification in Charcot– Marie– Tooth disease type 1A

Tao

Beecham

Rebelo

et al. 2019

Annals of Neurology

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Objective: Genetic modifiers in rare disease have long been suspected to contribute to the considerable variance in disease expression, including Charcot-Marie-Tooth disease type 1A (CMT1A). To address this question, the Inherited Neuropathy Consortium collected a large standardized sample of such rare CMT1A patients over a period of 8 years. CMT1A is caused in most patients by a uniformly sized 1.5 Mb duplication event involving the gene PMP22. Methods: We genotyped DNA samples from 971 CMT1A patients on Illumina BeadChips. Genome-wide analysis was performed in a subset of 330 of these patients, who expressed the extremes of a hallmark symptom: mild and severe foot dorsiflexion strength impairment. SIPA1L2 (signal-induced proliferation-associated 1 like 2), the top identified candidate modifier gene, was expressed in the peripheral nerve, and our functional studies identified and confirmed interacting proteins using coimmunoprecipitation analysis, mass spectrometry, and immunocytochemistry. Chromatin immunoprecipitation and in vitro siRNA experiments were used to analyze gene regulation. Results: We identified significant association of 4 single nucleotide polymorphisms (rs10910527, rs7536385, rs4649265, rs1547740) in SIPA1L2 with foot dorsiflexion strength (p < 1 × 10 −7 ). Coimmunoprecipitation and mass spectroscopy studies identified β-actin and MYH9 as SIPA1L2 binding partners. Furthermore, we show that SIPA1L2 is part of a View this article online at wileyonlinelibrary.com.

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Differential Sox10 genomic occupancy in myelinating glia

Lopez‐Anido

Sun

Koenning

et al. 2015

Glia

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138

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Myelin is formed by specialized myelinating glia: oligodendrocytes and Schwann cells in the central and peripheral nervous systems, respectively. While there are distinct developmental aspects and regulatory pathways in these two cell types, myelination in both systems requires the transcriptional activator Sox10. Sox10 interacts with cell type-specific transcription factors at some loci to induce myelin gene expression, but it is largely unknown how Sox10 transcriptional networks globally compare between oligodendrocytes and Schwann cells. We used in vivo ChIP-Seq analysis of spinal cord and peripheral nerve (sciatic nerve) to identify unique and shared Sox10 binding sites and assess their correlation with active enhancers and transcriptional profiles in oligodendrocytes and Schwann cells. Sox10 binding sites overlap with active enhancers and critical cell type-specific regulators of myelination, such as Olig2 and Myrf in oligodendrocytes, and Egr2/Krox20 in Schwann cells. Sox10 sites also associate with genes critical for myelination in both oligodendrocytes and Schwann cells, and are found within super-enhancers previously defined in brain. In Schwann cells, Sox10 sites contain binding motifs of putative partners in the Sp/Klf, Tead, and nuclear receptor protein families. Specifically, siRNA analysis of nuclear receptors Nr2f1 and Nr2f2 revealed downregulation of myelin genes Mbp and Ndrg1 in primary Schwann cells. Our analysis highlights different mechanisms that establish cell type-specific genomic occupancy of Sox10, which reflects the unique characteristics of oligodendrocyte and Schwann cell differentiation.

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Dynamic Regulation of Schwann Cell Enhancers after Peripheral Nerve Injury

Cited by 107 publications

References 94 publications

Regulation of Peripheral Nerve Myelin Maintenance by Gene Repression through Polycomb Repressive Complex 2

Regulation of Peripheral Nerve Myelin Maintenance by Gene Repression through Polycomb Repressive Complex 2

Variation in SIPA1L2 is correlated with phenotype modification in Charcot– Marie– Tooth disease type 1A

Differential Sox10 genomic occupancy in myelinating glia

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