Abstract
ABSTRACTThe DNA methylome is re-patterned during discrete phases of vertebrate development. In zebrafish, there are 2 waves of global DNA demethylation and re-methylation: the first occurs before gastrulation when the parental methylome is changed to the zygotic pattern and the second occurs after formation of the embryonic body axis, during organ specification. The occupancy of the histone variant H2A.Z and regions of DNA methylation are generally anti-correlated, and it has been proposed that H2A.Z restricts the boundaries of highly methylated regions. While many studies have described the dynamics of methylome changes during early zebrafish development, the factors involved in establishing the DNA methylation landscape in zebrafish embryos have not been identified. We test the hypothesis that the zebrafish ortholog of H2A.Z (H2afv) restricts DNA methylation during development. We find that, in control embryos, bulk genome methylation decreases after gastrulation, with a nadir at the bud stage, and peaks during mid-somitogenesis; by 24 hours post -fertilization, total DNA methylation levels return to those detected in gastrula. Early zebrafish embryos depleted of H2afv have significantly more bulk DNA methylation during somitogenesis, suggesting that H2afv limits methylation during this stage of development. H2afv deficient embryos are small, with multisystemic abnormalities. Genetic interaction experiments demonstrate that these phenotypes are suppressed by depletion of DNA methyltransferase 1 (Dnmt1). This work demonstrates that H2afv is essential for global DNA methylation reprogramming during early vertebrate development and that embryonic development requires crosstalk between H2afv and Dnmt1.
Highlights
How the epigenome of gametes becomes reprogrammed in zygotes to allow response to signals that regulate cell potency and fate is a central and unanswered question in epigenetics and developmental biology
Using primers that detect both paralogs, we found high levels of h2afva/h2afvb mRNA throughout development (Fig. 1A)
The zygotic epigenome is substantially re-patterned during early development, but little is known about the dynamics of the methylome during later development or how the pattern of methylation is set in embryos
Summary
How the epigenome of gametes becomes reprogrammed in zygotes to allow response to signals that regulate cell potency and fate is a central and unanswered question in epigenetics and developmental biology. Other regions, including the CpG islands that characterize most promoters, are protected from methylation.[1,2] While most of the methylome is static across cell types of the same species and across developmental time,[3,4,5,6] different cells have locus-specific differences in methylation levels, and this pattern is essential for embryonic development and developing cell identity.[7,8,9] In most vertebrates, the methylation pattern in the maternal and paternal gametes is erased following fertilization[10,11,12,13] and, subsequently, the zygotic methylation pattern is set and re-patterned as cell fate is established.[12] there are exceptions, as some non-imprinted regions of the genome, such as intracisternal
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