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

Abstract

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.

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

“…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 ]. This is due to impaired repression of Igfbp2 that maintains the activation of Akt-dependent myelination [50 ].…”

“…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 ]. This is due to impaired repression of Igfbp2 that maintains the activation of Akt-dependent myelination [50 ]. However, no defect in developmental myelination occurs in Eed mutants [50 ].…”

“…This is due to impaired repression of Igfbp2 that maintains the activation of Akt-dependent myelination [50 ]. However, no defect in developmental myelination occurs in Eed mutants [50 ]. A third study conducted in SC cultures proposes that loss of EZH2 leads in contrast to the inhibition of the myelination process through impaired inactivation of p75kip2 transcription that promotes expression of the inhibitor of myelination Hes5 [51].…”

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

“…Accordingly, RNA-seq analysis (described below) did not identify changes in ERK-dependent injury genes. Our previous analysis of uninjured nerves had revealed an increase in p-AKT in the cKO (Ma et al 2015), and at 1 d after injury, there was a similar increase in AKT phosphorylation at Thr308 and Ser473, which are catalyzed by PDK1 and mTORC2, respectively (Andjelković et al 1997; Sarbassov et al 2005) (Figure 2). At 1 d after injury, there is little change in p-AKT in wild type mice (Norrmén et al 2018; Ronchi et al 2016).…”

“…H3K27 methylation is catalyzed by Polycomb Repressive Complex 2 (PRC2), comprising the lysine methyltransferase EZH1/2 and the nonredundant core subunits, suppressor of zeste 12 (SUZ12) and embryonic ectoderm development (EED). EED is not required during Schwann cell development and myelination (Ma et al 2015), although there is Remak bundle disruption and hypermyelination in older EED deficient mice. Gene expression analyses, however, revealed a premature derepression of some injury-response genes in uninjured Eed cKO nerves.…”