Interactions of Sox10 and Egr2 in myelin gene regulation

Abstract

Myelination in the PNS is accompanied by a large induction of the Myelin Protein Zero (Mpz) gene to produce the most abundant component in peripheral myelin. Analyses of knockout mice have shown that the EGR2/Krox20 and SOX10 transcription factors are required for Mpz expression. Our recent work has shown that the dominant EGR2 mutations associated with human peripheral neuropathies cause disruption of EGR2/SOX10 synergy at specific sites, including a conserved enhancer element in the first intron of the Mpz gene. Further investigation of Egr2/Sox10 interactions reveals that activation of the Mpz intron element by Egr2 requires both Sox10-binding sites. In addition, both Egr1 and Egr3 cooperate with Sox10 to activate this element, which indicates that this capacity is conserved among Egr family members. Finally, a conserved composite structure of Egr2/ Sox10-binding sites in the genes encoding Mpz, Myelin-associated glycoprotein (Mag), and Myelin Basic Protein (Mbp) genes was used to screen for similar modules in other myelin genes, revealing a potential regulatory element in the periaxin gene. Overall, these results elucidate a working model for developmental regulation of Mpz expression, several facets of which extend to regulation of other peripheral myelin genes.

Desert Hedgehog Links Transcription Factor Sox10 to Perineurial Development

“…Both sites are separated by 11 bp, and the distance between their centers corresponds exactly to two helical turns. This is closer than most previously identified composite binding elements for Sox10 and Krox20 (Jones et al, 2007). It also differs from previously identified sites in that it combines the Krox20 site with a monomeric rather than a dimeric Sox10 binding site.…”

“…Sox10 activates the expression of peripheral myelin genes during terminal differentiation, including Mag, Mbp, Mpz, Pmp22, and Connexin 32 (Peirano et al, 2000;Bondurand et al, 2001;Jones et al, 2007. Sox10 is also directly involved in the activation of Krox20, which is a key activator of peripheral myelin genes (Ghislain and Charnay, 2006;Reiprich et al, 2010).…”

Dynamic Regulation of Schwann Cell Enhancers after Peripheral Nerve Injury

“…An example is shown for the myelin-associated glycoprotein (Mag) gene (Fig. 5A), which was previously shown to have Egr2 and Sox10 binding within a conserved intronic region (39,40,42). These sites are flanked by H3K27ac, but the active histone mark is practically abolished at 3 days after nerve injury.…”

“…Our previous genomic analysis revealed that 5-10% of Egr2-and Sox10-binding sites colocalize (depending on spacing) in peripheral nerve (51), reflecting "composite elements" that have been identified in several myelin genes, including Gjb1, Pmp22, Mbp, Mag, and Mpz (11)(12)(13)(14)(15)(16)39). When sites of Egr2/Sox10 colocalization were examined in the context of active enhancer marks, the majority (73%) of the composite Egr2 and Sox10 peaks were marked with H3K27ac in the sham condition.…”

SOX10 regulates an alternative promoter at the Charcot-Marie-Tooth disease locusMTMR2

“…Furthermore, this region is recognized by an antibody against H3K27Ac (31), which marks active regulatory elements, and by an antibody against H3K4me3, indicative of an active promoter element ( Figure 4A). These findings led us to analyse this region for binding by EGR2/ KROX20, which is a transcription factor that works synergistically with SOX10 at adjacent binding sites to regulate gene expression during myelination (32,33). This did not reveal any evidence of EGR2/KROX20 binding within the alternative promoter or anywhere else at MTMR2 (data not shown).…”