The landscape of accessible chromatin in mammalian preimplantation embryos

Abstract

In mammals, extensive chromatin reorganization is essential for reprogramming terminally committed gametes to a totipotent state during preimplantation development. However, the global chromatin landscape and its dynamics in this period remain unexplored. Here we report a genome-wide map of accessible chromatin in mouse preimplantation embryos using an improved assay for transposase-accessible chromatin with high throughput sequencing (ATAC-seq) approach with CRISPR/Cas9-assisted mitochondrial DNA depletion. We show that despite extensive parental asymmetry in DNA methylomes, the chromatin accessibility between the parental genomes is globally comparable after major zygotic genome activation (ZGA). Accessible chromatin in early embryos is widely shaped by transposable elements and overlaps extensively with putative cis-regulatory sequences. Unexpectedly, accessible chromatin is also found near the transcription end sites of active genes. By integrating the maps of cis-regulatory elements and single-cell transcriptomes, we construct the regulatory network of early development, which helps to identify the key modulators for lineage specification. Finally, we find that the activities of cis-regulatory elements and their associated open chromatin diminished before major ZGA. Surprisingly, we observed many loci showing non-canonical, large open chromatin domains over the entire transcribed units in minor ZGA, supporting the presence of an unusually permissive chromatin state. Together, these data reveal a unique spatiotemporal chromatin configuration that accompanies early mammalian development.

Exposure to the widely used herbicide atrazine results in deregulation of global tissue-specific RNA transcription in the third generation and is associated with a global decrease of histone trimethylation in mice

“…It has been shown that NR5A2 binds directly to both promoter and enhancer regions in Pou5f1 and activates its expression (128). Nr5a2 is highly expressed during development and the knockdown of Nr5a2 in zygote leads to downregulation of Pou5f1 expression (24). In our previous work we showed that mice exposed to ATZ have a higher number of H3K4me3 peaks that contain Nr5a2 motif (42).…”

“…Our model predicts that the changes in germ cells induced by ATZ will be preserved at limited genomic regions. Specifically, we propose that the genes, which are expressed from both paternal and maternal alleles in the very early zygote (such as Pou5f1, Nr5a2, Klf2 ) are required to be in an open chromatin state (24) that likely preserves their histones as well as the histone modifications. Other potential candidates to mediate ATZ effects are ATP-binding proteins, since human sperm nucleosome fraction of genome is enriched in genes encoding them (20).…”

“…Other potential candidates to mediate ATZ effects are ATP-binding proteins, since human sperm nucleosome fraction of genome is enriched in genes encoding them (20). The genes for proteins with chromatin modifications function, which have open chromatin state at distally located promoters and are essential for establishment of early pluripotent state (24) are also among the most plausible candidates.…”

“…However, whether this mechanism is conserved in vertebrates, is uncertain. A recent work showed that accessible chromatin in early mouse embryos is both of the maternal and paternal origins (24) and implicated paternal sperm histone function in early zygote. H3K4me3 is found to be strongly associated with both maternal and paternal genomes in mouse, rabbit and bovine zygote (25).…”

“…However, the role of retroelements in transgenerational inheritance was also demonstrated independently in case of Intracisternal A-particle retroelements (27). Recent work showed that the accessible chromatin landscape in early embryos is extensively shaped by transposable elements (24). …”