Chromatin remodeling in bovine embryos indicates species-specific regulation of genome activation

Michelle M Halstead,Richard M Schultz,Chuan Zhou,Xin Ma,Pablo J Ross

doi:10.1038/s41467-020-18508-3

Abstract

The shift from maternal to embryonic control is a critical developmental milestone in preimplantation development. Widespread transcriptomic and epigenetic remodeling facilitate this transition from terminally differentiated gametes to totipotent blastomeres, but the identity of transcription factors (TF) and genomic elements regulating embryonic genome activation (EGA) are poorly defined. The timing of EGA is species-specific, e.g., the timing of murine and human EGA differ significantly. To deepen our understanding of mammalian EGA, here we profile changes in open chromatin during bovine preimplantation development. Before EGA, open chromatin is enriched for maternal TF binding, similar to that observed in humans and mice. During EGA, homeobox factor binding becomes more prevalent and requires embryonic transcription. A cross-species comparison of open chromatin during preimplantation development reveals strong similarity in the regulatory circuitry underlying bovine and human EGA compared to mouse. Moreover, TFs associated with murine EGA are not enriched in cattle or humans, indicating that cattle may be a more informative model for human preimplantation development than mice.

Highlights

The shift from maternal to embryonic control is a critical developmental milestone in preimplantation development
A subset of embryos from each collection was cultured in the presence of the transcriptional inhibitor, α-amanitin, to interrogate the relationship between embryonic transcription and chromatin remodeling (Fig. 1a)
Between 30 and 87 million nonmitochondrial monoclonal uniquely mapped reads were collectively obtained for each developmental stage and cell type: germinal vesicle-stage (GV) oocytes, 2, 4, 8-cell embryos, morula, inner cell masses (ICM), and embryonic stem cells (ESC)[37] (Supplementary Table 1)

Summary

Introduction

The shift from maternal to embryonic control is a critical developmental milestone in preimplantation development. The cleavage-stage embryo must first complete the maternal-to-zygotic transition (MZT), wherein the embryo assumes control over its own continued development by degrading oocyte-derived products and initiating its own transcriptional program This dramatic change in gene expression proceeds gradually; minor embryonic genome activation (EGA) results in low levels of transcription in early cleavagestage embryos[1,2], and leads to major EGA, which involves widespread transcription of embryonic genes[3]. This shift from maternal dependence to self-sufficiency serves at least three functions: elimination of oocyte-specific messages, replenishment of transcripts that are common to both the oocyte and the embryo, and generation of novel embryonic-specific transcripts[4]. In mouse and human preimplantation embryos, enrichment for chromatin accessible sites is gradually established as development progresses[17,18,19,20,21,22]; these accessible sites demonstrate different motif enrichment patterns, implicating distinct sets of transcription factors (TFs) in either murine (RARG, NR5A2, ESRRB)[17], or human EGA (OTX2, GSC, POU5F1)[18,20]

Methods

Results

Conclusion