Broad histone H3K4me3 domains in mouse oocytes modulate maternal-to-zygotic transition

Abstract

Maternal-to-zygotic transition (MZT) is essential for the formation of a new individual, but is still poorly understood despite recent progress in analysis of gene expression and DNA methylation in early embryogenesis1–9. Dynamic histone modifications may have important roles in MZT10–13, but direct measurements of chromatin states have been hindered by technical difficulties in profiling histone modifications from small quantities of cells. Recent improvements allow for 500 cell-equivalents of chromatin per reaction, but require 10,000 cells for initial steps14 or require a highly specialized microfluidics device that is not readily available15. We developed a micro-scale chromatin immunoprecipitation and sequencing (μChlP-seq) method, which we used to profile genome-wide histone H3 lysine methylation (H3K4me3) and acetylation (H3K27ac) in mouse immature and metaphase II oocytes and in 2-cell and 8-cell embryos. Notably, we show that ~22% of the oocyte genome is associated with broad H3K4me3 domains that are anti-correlated with DNA methylation. The H3K4me3 signal becomes confined to transcriptional-start-site regions in 2-cell embryos, concomitant with the onset of major zygotic genome activation. Active removal of broad H3K4me3 domains by the lysine demethylases KDM5A and KDM5B is required for normal zygotic genome activation and is essential for early embryo development. Our results provide insight into the onset of the developmental program in mouse embryos and demonstrate a role for broad H3K4me3 domains in MZT.

Zygotic Genome Activation in Vertebrates

“…Histone modifications in mammalian early embryos have also recently been measured genome-wide (Dahl et al, 2016; Liu et al, 2016; Zhang et al, 2016). In mouse oocytes, prior to the ZGA, the “active” mark, H3K4me3, which is normally found in sharp peaks at transcription start sites (TSS), was present in broad 5–10kb domains over loci (Fig.…”

“…These “non-canonical” H3K4me3 domains became restricted to the TSS only at the 2-cell stage, concurrent with mouse ZGA. Since ZGA is required for removal of these broad domains, they may be remnants of prior transcription, or even exist as a “repressive” mark to keep these loci silenced before the ZGA (Dahl et al, 2016). Notably, loss of H3K4me3 results in loss of paternal pronuclear ZGA in mouse (Aoshima et al, 2015).…”

JARID1 Histone Demethylases: Emerging Targets in Cancer

“…In embryogenesis, JARID1A and JARID1B have functions in activating the zygotic genome [108], and their expression subsequently peaks at the blastocyst stage. Although JARID1B was once thought to be required for ESC self-renewal, this view is contradicted by JARID1B knockout producing normal or enhanced ESC self-renewal and marker expression [109].…”

Setd1b, encoding a histone 3 lysine 4 methyltransferase, is a maternal effect gene required for the oogenic gene expression program

“…In the female gonad, primary oocytes are arrested in prophase of meiosis I at birth (Edson et al, 2009). Subsequently they enlarge, accumulate transcripts needed for early embryonic development and undergo notable changes in chromatin configuration accompanied by epigenetic changes including alterations of lysine methylation on the histone 3 tail and re-establishment of DNA methylation (Stewart et al, 2015;Dahl et al, 2016;Liu et al, 2016;Zhang et al, 2016).…”