Nuc‐ErbB3 regulates H3K27me3 levels and HMT activity to establish epigenetic repression during peripheral myelination

Ness, Jennifer K.; Skiles, Amanda A.; Yap, Eng Hui; Fajardo, Eduardo; Fiser, András; Tapinos, Nikos

doi:10.1002/glia.22977

Cited by 9 publications

(9 citation statements)

References 57 publications

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“…Ness and colleagues (2016) identify Nuc-ErbB3, a nuclear variant of ErbB3, as a DNA-binding protein that promotes H3K27me3 at gene promoters presumably by activating the HMT EZH2. This study reports that loss of Nuc-ErbB3 (constitutive mouse mutant) leads to developmental hypermyelination [49]. Consistently, ablation of the PRC2 subunit Eed in immature SCs (using floxed Eed and P0-Cre mouse lines), that leads to inactivation of the PRC2 complex (mediating H3K27me3 through its HMT EZH2), results in hypermyelination in adults [50 ].…”

Section: Involvement Of Repressive Histone Methylation Marks In Regulsupporting

confidence: 64%

Chromatin-remodeling enzymes in control of Schwann cell development, maintenance and plasticity

Jacob

2017

Current Opinion in Neurobiology

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Gene regulation is essential for cellular differentiation and plasticity. Schwann cells (SCs), the myelinating glia of the peripheral nervous system (PNS), develop from neural crest cells to mature myelinating SCs and can at early developmental stage differentiate into various cell types. After a PNS lesion, SCs can also convert into repair cells that guide and stimulate axonal regrowth, and remyelinate regenerated axons. What controls their development and versatile nature? Several recent studies highlight the key roles of chromatin modifiers in these processes, allowing SCs to regulate their gene expression profile and thereby acquire or change their identity and quickly react to their environment. AddressDepartment of Biology, University of Fribourg, Chemin du Musé e 10, 1700 Fribourg, SwitzerlandCorresponding author: Jacob, Claire (claire.jacob@unifr.ch) IntroductionSCs originate from neural crest cells that also give rise to other cell types including sensory neurons, chondrocytes, melanocytes, smooth-muscle cells [1,2]. After specification in SC precursors, the lineage further differentiates into immature SCs that encircle bundles of axons of different calibers. Next, big caliber axons are sorted in a one-to-one relationship with SCs by a process called radial sorting which leads to the promyelinating stage. The last step of maturation is the myelination process where SCs build a thick myelin sheath rich in lipids around axons (Figure 1). Meanwhile, small caliber axons remain in bundles associated with non-myelinating SCs and persist as Remak bundles in adult nerves [3,4]. Myelin provides axonal insulation and fast conduction of electric signals along axons; its formation and maintenance are thus critical for neuronal functions. By contrast, myelin is detrimental for axonal regrowth after lesion, because it contains growth inhibitory proteins [5]. However, SCs react quickly to an axonal lesion by dedifferentiating, digesting their own myelin -a process called myelinophagy [6] -and converting into repair cells [7,8] that foster axonal regrowth and guide axons back to their former target [9,10]. SCs then remyelinate regenerated axons (Figure 2). This remarkable SC plasticity allows the PNS to functionally regenerate after lesion.This review is focused on the mechanisms of SC development, maintenance and plasticity after lesion controlled by chromatin-remodeling enzymes. Chromatin remodeling regulates the accessibility of genes for the transcriptional machinery, and thereby gene activation and repression. Changes of chromatin architecture are controlled by ATP-dependent nucleosome remodeling and by covalent modifications, either on DNA by methylation or on histones by various post-translational modifications including acetylation, methylation, phosphorylation, ubiquitination, SUMOylation, ADP-ribosylation. Although our knowledge on these mechanisms is still very sparse, recent findings on the functions of chromatinremodeling enzymes have significantly contributed to a better understanding of their critical fu...

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Section: Involvement Of Repressive Histone Methylation Marks In Regulsupporting

confidence: 64%

Chromatin-remodeling enzymes in control of Schwann cell development, maintenance and plasticity

Jacob

2017

Current Opinion in Neurobiology

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“…By analyzing the promoters of the type I and type III transcripts of Nrg1 , we found that H3K27me3 mediates repression of Nrg1 and there is increased expression of the type I Nrg1 transcript in the uninjured Eed cKO nerves, indicating a mechanism by which type I Nrg1 is repressed in uninjured nerve. Interestingly, NRG1 increases the expression of nuc-ErbB3 (a nuclear variant of the NRG1 receptor, ErbB3), which has transcriptional activity by modulating H3K27me3 level in Schwann cells (Adilakshmi et al 2011; Ness et al 2016). However, nuc-ErbB3 likely has other activities since the phenotype and gene expression changes that we observe in the Eed knockout differ in several respects.…”

Section: Discussionmentioning

confidence: 99%

“…Gray shading indicates H3K27me3 occupancy of genes in peripheral nerves of uninjured or post-injury conditions. See Supporting Information Table 6 for expression fold changes by Eed cKO among PRC2-deficient MPNST genes and H3K27me3 peak score [Color figure can be viewed at wileyonlinelibrary.com] expression of nuc-ErbB3 (a nuclear variant of the NRG1 receptor, ErbB3), which has transcriptional activity by modulating H3K27me3 level in Schwann cells (Adilakshmi, Ness-Myers, Madrid-Aliste, Fiser, & Tapinos, 2011;Ness et al, 2016). However, nuc-ErbB3 likely has other activities since the phenotype and gene expression changes that we observe in the Eed knockout differ in several respects.…”

Section: Discussionmentioning

confidence: 99%

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

Duong

Moran

et al. 2018

Glia

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The transition of differentiated Schwann cells to support of nerve repair after injury is accompanied by remodeling of the Schwann cell epigenome. The EED-containing polycomb repressive complex 2 (PRC2) catalyzes histone H3K27 methylation and represses key nerve repair genes such as Shh, Gdnf and Bdnf, and their activation is accompanied by loss of H3K27 methylation. Analysis of nerve injury in mice with a Schwann cell-specific loss of EED showed the reversal of polycomb repression is required and a rate limiting step in the increased transcription of Neuregulin 1 (type I), which is required for efficient remyelination. However, mouse nerves with EED-deficient Schwann cells display slow axonal regeneration with significantly low expression of axon guidance genes, including Sema4f and Cntf. Finally, EED loss causes impaired Schwann cell proliferation after injury with significant induction of the Cdkn2a cell cycle inhibitor gene. Interestingly, PRC2 subunits and CDKN2A are commonly co-mutated in the transition from benign neurofibromas to malignant peripheral nerve sheath tumors (MPNST’s). RNA-seq analysis of EED-deficient mice identified PRC2-regulated molecular pathways that may contribute to the transition to malignancy in neurofibromatosis.

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“…In Nuc‐ErbB3 knockin mouse, which is a variant of ERBB3 that is expressed in the nucleus of Schwann cells, Ness found that NUC‐ERBB3 could significantly decrease the activation of histone H3K27me3 methyltransferase (HMT), reduce level of H3K27me3, and eventually lead to aberrant myelination (Ness et al., ).…”

Section: Other Histone Modifications In Myelinating Cellsmentioning

confidence: 99%

“…In Nuc-ErbB3 knockin mouse, which is a variant of ERBB3 that is expressed in the nucleus of Schwann cells, Ness found that NUC-ERBB3 could significantly decrease the activation of histone H3K27me3 methyltransferase (HMT), reduce level of H3K27me3, and eventually lead to aberrant myelination (Ness et al, 2016). Petrilli et al (2013) Except for lysine methylation, protein arginine methyltransferase, PRMT1 and PRMT5, have been identified playing critical roles during OL differentiation.…”

Section: Modifications In Myelinating Cellsmentioning

confidence: 99%

Epigenetic regulation of myelination in health and disease

Zhang

Wang

et al. 2019

Eur J of Neuroscience

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Myelin is lipid‐rich structure that is necessary to avoid leakage of electric signals and to ensure saltatory impulse conduction along axons. Oligodendrocytes in central nervous system (CNS) and Schwann cells in peripheral nervous system (PNS) are responsible for myelin formation. Axonal demyelination after injury or diseases greatly impairs normal nervous system function. Therefore, understanding how the myelination process is programmed, coordinated, and maintained is crucial for developing therapeutic strategies for remyelination in the nervous system. Epigenetic mechanisms have been recognized as a fundamental contributor in this process. In recent years, histone modification, DNA modification, ATP‐dependent chromatin remodeling, and non‐coding RNA modulation are very active area of investigation. We will present a conceptual framework that integrates crucial epigenetic mechanisms with the regulation of oligodendrocyte and Schwann cell lineage progression during development and myelin degeneration in pathological conditions. It is anticipated that a refined understanding of the molecular basis of myelination will aid in the development of treatment strategies for debilitating disorders that involve demyelination, such as multiple sclerosis in the CNS and neuropathies in the PNS.

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Nuc‐ErbB3 regulates H3K27me3 levels and HMT activity to establish epigenetic repression during peripheral myelination

Cited by 9 publications

References 57 publications

Chromatin-remodeling enzymes in control of Schwann cell development, maintenance and plasticity

Chromatin-remodeling enzymes in control of Schwann cell development, maintenance and plasticity

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

Epigenetic regulation of myelination in health and disease

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