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

Abstract

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...

Repair Schwann cell update: Adaptive reprogramming, EMT, and stemness in regenerating nerves

“…This includes the Rac1–MKK7–JNK pathway and mTORC, which elevate c‐Jun and have been implicated as upstream activators of c‐Jun after nerve injury, and the cAMP pathway that suppresses c‐Jun (Arthur‐Farraj et al, ; Monje, Soto, Bacallao, & Wood, ; Norrmén et al, ; Shin et al, ). Histone deacetylase 2 (HDAC2), which is activated in injured nerves, also downregulates c‐Jun (Brügger et al, ; reviewed in Jacob, ). The transcription factors Krox20 and Oct6 also antagonize c‐Jun expression (Brügger et al, ; Parkinson et al, ).…”

“…Several epigenetic processes regulate the repair Schwann cell phenotype (Ma & Svaren, ; reviewed in Jacob, ). Injury sets in train chromatin remodeling involving, first, the loss of the active histone mark H3K27 acetylation on enhancers of a number of myelin genes.…”

“…Interestingly, macrophage recruitment and Schwann cell numbers, at least at early time points after injury, are less affected in the absence of c-Jun than other aspects of the injury response(Arthur-Farraj et al, 2012). A microarray screening shows that c-Jun controls 172 genes, including directly regulating several neurotrophic factors such as GDNF, BDAF, Shh, and Artemin(Arthur-Farraj et al, 2012;Fontana et al, 2012).However, after nerve injury microarray and RNA-Seq analysis demonstrate at least 4,000-5,000 differentially expressed RNAs, showing that c-Jun only controls a subset of injury induced genes(Arthur- Farraj et al, 2012, 2017Barrette, Calvo, Vallières, & Lacroix, 2010;Bosse, Hasenpusch-Theil, Küry, & Müller, 2006;Chang et al, 2013;Nagarajan, Le, Mahoney, Araki, & Milbrandt, 2002).The extracellular signals that activate Schwann cell c-Jun after injury are obscure. Nevertheless, a number of intracellular pathways that potentially regulate c-Jun levels have been identified.…”

Transcriptional control of myelination and remyelination

“…These have been catalogued in several recent reviews (Küspert & Wegner, ; Stolt & Wegner, ; Svaren & Meijer, ). Similarly, chromatin modifying activities and regulatory RNAs have been identified as important regulators in both types of myelinating glia (Gregath & Lu, ; Jacob, ; Svaren, ). In this review, we will concentrate on transcription factors and put the focus on the functional interactions within their networks.…”

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

“…It has become clear that epigenomic changes are important for such reprogramming events, employing mechanisms of gene activation and derepression (Brügger et al 2017; He et al 2018; Hung et al 2015; Jacob 2017; Ma and Svaren 2018). Our previous studies identified the association of trimethylation at Lys27 of histone H3 tail (H3K27me3) at promoters of many genes that become activated after peripheral nerve injury, and we found that the demethylation is required for full activation of some repair genes (Ma et al 2016).…”