Snail2/Slug cooperates with Polycomb repressive complex 2 (PRC2) to regulate neural crest development

Abstract

Neural crest cells arise from the border of the neural plate and epidermal ectoderm, migrate extensively and differentiate into diverse cell types during vertebrate embryogenesis. Although much has been learnt about growth factor signals and gene regulatory networks that regulate neural crest development, limited information is available on how epigenetic mechanisms control this process. In this study, we show that Polycomb repressive complex 2 (PRC2) cooperates with the transcription factor Snail2/Slug to modulate neural crest development in Xenopus. The PRC2 core components Eed, Ezh2 and Suz12 are expressed in the neural crest cells and are required for neural crest marker expression. Knockdown of Ezh2, the catalytic subunit of PRC2 for histone H3K27 methylation, results in defects in neural crest specification, migration and craniofacial cartilage formation. EZH2 interacts directly with Snail2, and Snail2 fails to expand the neural crest domains in the absence of Ezh2. Chromatin immunoprecipitation analysis shows that Snail2 regulates EZH2 occupancy and histone H3K27 trimethylation levels at the promoter region of the Snail2 target E-cadherin. Our results indicate that Snail2 cooperates with EZH2 and PRC2 to control expression of the genes important for neural crest specification and migration during neural crest development.

High Glucose-Induced Reactive Oxygen Species Stimulates Human Mesenchymal Stem Cell Migration Through Snail and EZH2-Dependent E-Cadherin Repression

“…EZH2 has been considered an essential factor for epigenetic regulation of E-cadherin [43]. Binding of PRC2 members, such as EZH2, Suz12, and EED, to the promoter of target gene induces epigenetic regulation that is regulated by Snail, which cooperates with PRC2 [43, 52, 70, 71]. Snail is also required for EZH2-mediated E-cadherin repression and the complex of EZH2/HDAC/Snail contributed to E-cadherin silencing in carcinomas [72, 73].…”

Mutation Spectra of Histone Methyltransferases With Canonical SET Domains and EZH2-Targeted Therapy

“…EZH2 directly interacts with β-catenin [73], DNMT1, DNMT3A, DNMT3B [74], EED [58], ERα [73], GATA4 [69], NF-κB [75], PCNAassociated factor (KIAA0101) [76], SNAI2 (Slug) [77] and SUZ12 [58]. Although the mechanisms underlying these interactions remain unclear, EZH2 also interacts with the androgen receptor (AR) [78], ASXL1 [79], FOXP3 [80] and REST [81].…”

“…CDKN2A repression subsequently leads to EZH2 upregulation through CDK4/6-mediated E2F activation; these events constitute the E2F/ EZH2 positive-feedback loop. EZH2 also interacts with SNAI2 to repress the CDH1 gene, which encodes E-cadherin [77]. EZH2 also interacts with other non-PRC2 proteins to transcriptionally activate the target genes of the β-catenin-TCF/LEF complex (MYC and CCND1, among others) [73,76] and of NF-κB (IL-6, TNF, NOTCH1, among others) [75,85].…”

“…For example, EZH2-dependent transcriptional activation of MYC/CCND1 and repression of CDKN2A leads to tumor proliferation and survival [73,82]; EZH2-dependent CDH1 repression induces epithelial-to-mesenchymal transition, and subsequent invasion and metastasis [77]; EZH2-dependent transcriptional activation of IL-6/TNF and repression of IFNGR1 also promotes tumorigenesis through maintenance of chronic inflammation [75] and establishment of tumor immune tolerance [84], respectively (Figure 4). …”

Epigenetics in ENS development and Hirschsprung disease

“…Recently, it has been described the opposite function of the two isoforms of AEBP2 (DNA-binding repressor for the aP2) on PCR2 expression and, consequently, on neural crest cell migration during development (Kim et al, 2015). Likewise, it has been also shown that Snail/Slug cooperates with PRC2 in the regulation of NCCs development (Tien et al, 2015).…”