Inherited DNA methylation primes the establishment of accessible chromatin during genome activation

Abstract

For animals, epigenetic modifications can be globally or partially inherited from gametes after fertilization, and such information is required for proper transcriptional regulation, especially during the process of zygotic genome activation (ZGA). However, the mechanism underlying how the inherited epigenetic signatures affect transcriptional regulation during ZGA remains poorly understood. Here, we performed genome-wide profiling of chromatin accessibility during zebrafish ZGA, which is closely related to zygotic transcriptional regulation. We observed a clear trend toward a gradual increase in accessible chromatin during ZGA. Furthermore, accessible chromatin at the promoters displayed a sequential priority of emergence, and the locations of the accessible chromatin were precisely primed by the enrichment of unmethylated CpGs that were fully inherited from gametes. On the other hand, distal regions with high methylation levels that were inherited from the sperm facilitated the binding of DNA methylation-preferred transcription factors, such as Pou5f3 and Nanog, which contributed to the establishment of accessible chromatin at these loci. Our results demonstrate a model whereby inherited DNA methylation signatures from gametes prime the establishment of accessible chromatin during zebrafish ZGA through two distinct mechanisms.

Chromatin accessibility established by Pou5f3, Sox19b and Nanog primes genes for activity during zebrafish genome activation

“…Our results are in agreement with two recent studies reporting that the genetic loss of pou5f3 and nanog, or their knockdown by translation-blocking morpholinos, influences the accessibility of chromatin at sites bound by these factors [25,26]. In contrast to the previously reported preference of Pou5f3 and Nanog to open up distal regions that are DNA methylated [25], we find that Pou5f3, Sox19b and Nanog are also important for regulating chromatin accessibility at promoters of zygotic genes, which are generally hypomethylated. This might explain why a third study [26] found no preference for Pou5f3 and Nanog affecting accessibility at hypermethylated sites.…”

“…Our finding that chromatin accessibility increases during genome activation, especially at promoter and enhancer elements, is consistent with recent studies in Drosophila, zebrafish, Xenopus, mouse and human embryos [4,[10][11][12][13]25,49]. An increase in the number and strength of ATAC-seq peaks over time may either be due to an increase in the number of cells in which specific regions are accessible, or an actual increase in the accessibility of specific regions in all cells of the embryo.…”

“…Another potential mechanism involves the recruitment of chromatin remodelers to establish accessibility at regulatory elements. Recently, it was suggested that BRG1 could be involved in Pou5f3-mediated opening of chromatin in zebrafish [25], similar to what has been reported in ES cells [72]. However, it is likely that Pou5f3-mediated chromatin remodeling in zebrafish mechanistically differs from other species, given that zebrafish Pou5f3 lacks the linker region between the POU domains, which appears to be important for the interaction with Brg1…”

“…Our finding that regulatory elements can be accessible prior to transcription of associated genes is in agreement with the establishment of other "active" chromatin features prior to gene expression. At zebrafish promoters, for example, the histone modifications H3K4me3 [57,58] and H3K27ac [56,59], a hypomethylated state ( [25,[60][61][62], and well-positioned nucleosomes [63] can be established prior to the time their associated genes become expressed. Similar observations have been made in other species.…”

Genome‐scale sampling suggests cryptic epigenetic structuring and insular divergence in Canada lynx

“…Such hypotheses align with theoretical models of epigenetically mediated adaptive plasticity, although further empirical investigations in wild populations are merited (Greenspoon & Spencer, ). Provided that epigenetic patterns are maintained across generations (Colomé‐Tatché et al, ; Joo et al, ; Liu, Wang, Hu, Wang, & Zhang, ; Schmitz et al, ), DNA methylation could be integrated into the working model of ecological speciation with gene flow by mediating gene expression and the optimal phenotype under local conditions (Greenspoon & Spencer, ).…”