Active DNA demethylation at enhancers during the vertebrate phylotypic period

Abstract

The vertebrate body plan and organs are shaped during a conserved embryonic phase called the phylotypic stage. However, the mechanisms that guide the epigenome through this transition and their evolutionary conservation remain elusive. Here we report widespread DNA demethylation of enhancers during the phylotypic period in zebrafish, Xenopus tropicalis and mouse. These enhancers are linked to developmental genes that display coordinated transcriptional and epigenomic changes in the diverse vertebrates during embryogenesis. Binding of Tet proteins to (hydroxy)methylated DNA and enrichment of 5-hydroxymethylcytosine in these regions implicated active DNA demethylation in this process. Furthermore, loss of function of Tet1, Tet2 and Tet3 in zebrafish reduced chromatin accessibility and increased methylation levels specifically at these enhancers, indicative of DNA methylation being an upstream regulator of phylotypic enhancer function. Overall, our study highlights a regulatory module associated with the most conserved phase of vertebrate embryogenesis and suggests an ancient developmental role for Tet dioxygenases.

Cyst Nematode Parasitism Induces Dynamic Changes in the Root Epigenome

“…Recently, it has been demonstrated that binding sites for the tomato ripening inhibitor transcription factors were commonly localized in hypomethylated regions of the promoters of ripening-associated genes whose expression was increased concurrently with gradual deceases in DNA methylation (Zhong et al, 2013). Also, we do not rule out the possibility that, in some cases, binding of transcription factors to specific promoter regions may lead to active demethylation of these regions, as recently demonstrated in other systems (Stadler et al, 2011;Pacis et al, 2015;Bogdanovi c et al, 2016). In other words, DNA hypomethylation in some cases could be the consequence of gene up-regulation and not the cause.…”

Dysregulation of TET2 in hematologic malignancies

“…Our understanding of the effect of TET2 mutations thus remains incomplete. It has been shown, however, that in embryonic stem cells, Tet2 single [41] and Tet1/2/3 triple [42] knockout results in hypermethylation at selected enhancer regions.…”

5'-Hydroxymethylcytosine Precedes Loss of CpG Methylation in Enhancers and Genes Undergoing Activation in Cardiomyocyte Maturation

“…Despite recent evidence for attenuation of polymerase II transcription elongation by 5caC [19], the functional role of these later 5mC oxidation products still remains to be fully understood. Genome-wide mapping in a variety of tissues and cell types at different developmental time points suggest a role of 5hmC in DNA loss of CpG methylation at specific regulatory elements, namely enhancers [20–24]. Yet, only one report assessed 5hmC at more than one single time point during brain development in the mouse.…”

“…Besides its role as an intermediate in DNA loss of CpG methylation, 5hmC may also be an epigenetic mark with own regulatory functions. 5hmC was shown to be predominantly stable in various genomic contexts [23, 25–27] and to have its own reader proteins [20, 28–30]. In addition to enhancers [22, 26, 31–36], 5hmC was found to be enriched within gene bodies [22, 26, 32, 34, 35, 37].…”