DNA methyltransferase 3B regulates duration of neural crest production via repression of Sox10

Abstract

Neural crest stem cells arise within the central nervous system but then undergo an epithelial-to-mesenchymal transition to migrate away and contribute to the peripheral nervous system and craniofacial skeleton. Here we show that DNA methyltransferase 3B (DNMT3B) is responsible for the loss of competence of dorsal neural tube cells to generate emigrating neural crest cells. DNMT3B knockdown results in up-regulation of neural crest markers, prolonged neural crest emigration, and subsequent precocious neuronal differentiation of the trigeminal ganglion. We find that DNMT3B binds to the promoter of Sox10, known to be important for neural crest emigration and lineage acquisition. Bisulfite sequencing further reveals methylation of the Sox10 promoter region upon cessation of emigration in normal embryos, whereas this mark is reduced after DNMT3B loss. Taken together, these results reveal the importance of DNA methylation in regulating the ability of neural tube cells to produce neural crest cells and the timing of peripheral neuron differentiation.

Specifying neural crest cells: From chromatin to morphogens and factors in between

“…For example, Sox10 expression is regulated by both DNA methylation and histone methylation. DNMT3B binds to and methylates the promoter of Sox10 to regulate the duration of NC production (Hu, Strobl-Mazzulla, Simoes-Costa, et al, 2014). Conversely, histone demethylase KDM4A (JMJD2A), removes the H3K9me3 repressive mark at the promoters of Sox10 as well as several other NC specifiers (e.g., Snai2 , FoxD3 , Sox8 ) during NC specification (Matsukawa, Miwata, Asashima, & Michiue, 2015; Strobl-Mazzulla et al, 2010).…”

“…Access to the enhancers and promoters of NC genes is tightly regulated by a host of epigenetic modifiers in vivo and in vitro during the formation of NC cells (Rada-Iglesias et al, 2012). Multiple NC-related genes in chicken such as, Sox10 (Hu, Strobl-Mazzulla, Simoes-Costa, Sanchez-Vasquez, & Bronner, 2014; Jacques-Fricke & Gammill, 2014), Sox9 , Foxd3 , and Snai2 (Strobl-Mazzulla, Sauka-Spengler, & Bronner-Fraser, 2010), Sox2 and Sox3 (Hu, Strobl-Mazzulla, Sauka-Spengler, & Bronner, 2012), and Pax3 in mouse (Wei & Loeken, 2014), have been identified as targets of transcriptional control. At the chromatin level, recent studies in frog have shown that the Polycomb Repressive Complex (PRC) interacts with SNAI1/2 proteins to control the levels of histone H3K27 trimethylation on target promoters, which allows NC-promoting genes to be expressed (Tien et al, 2015).…”

“…At the chromatin level, recent studies in frog have shown that the Polycomb Repressive Complex (PRC) interacts with SNAI1/2 proteins to control the levels of histone H3K27 trimethylation on target promoters, which allows NC-promoting genes to be expressed (Tien et al, 2015). Additionally, DNA methyltransferase 3B (DNMT3B) methylates the SOX10 promoter region to control the duration of NC production, while DNMT3A binds to the promoter regions of Sox2 and Sox3 and represses them allowing for the formation of NC cells (Hu et al, 2012; Hu, Strobl-Mazzulla, Simoes-Costa, et al, 2014). Transcriptional control can range from availability of transcription factors and their partners to the presence of transcriptional elongation factors such as CDK9 and CYCLINT1 of the P-TEFβ complex, which are also required for NC specification (Hatch et al, 2016).…”

Transcriptomic profile analysis of mouse neural tube development by RNA‐Seq

“…DSGs were regulated by MXE, RI and SE in Brc8.5-vs-Brc10.5, and regulated by MXE, RI, SE and A3SS in Brc8.5-vs-Brc9.5 and Brc9.5-vs-Brc10.5 comparison. Among 29 DSGs, Ngrn, Ddr1, Dctn1, Dnmt3b, Ect2, Map2, Mbnl1, Meis2, Vcan and App were related with nervous system development (57)(58)(59)(60)(61)(62)(63)(64)(65)(66). Furthermore, Dnmt3b, a NTD candidate gene, was regulated by SE during neural tube development (67,68).…”

Comparison of DNA Methylation in Schwann Cells before and after Peripheral Nerve Injury in Rats

“…What is more, some studies [10] have reported that myelination of SCs can be regulated by DNA methylation process. Although previous studies [15, 16] have provided some clues for understanding the relationship between DNA methylation and gene regulation of SCs, due to the limitation of experimental technique, the mechanisms driving all of this still are not understood very well. In this study, for the first time, we comprehensively characterized the differences of genomewide DNA methylation expression regarding SCs before and after PNS injury by Methylated DNA Immunoprecipitation Sequencing (MeDIP-Seq).…”