Rewirable gene regulatory networks in the preimplantation embryonic development of three mammalian species

Abstract

Mammalian preimplantation embryonic development (PED) is thought to be governed by highly conserved processes. While it had been suggested that some plasticity of conserved signaling networks exists among different mammalian species, it was not known to what extent modulation of the genomes and the regulatory proteins could “rewire” the gene regulatory networks (GRN) that control PED. We therefore generated global transcriptional profiles from three mammalian species (human, mouse, and bovine) at representative stages of PED, including: zygote, two-cell, four-cell, eight-cell, 16-cell, morula and blastocyst. Coexpression network analysis suggested that 40.2% orthologous gene triplets exhibited different expression patterns among these species. Combining the expression data with genomic sequences and the ChIP-seq data of 16 transcription regulators, we observed two classes of genomic changes that contributed to interspecies expression difference, including single nucleotide mutations leading to turnover of transcription factor binding sites, and insertion of cis-regulatory modules (CRMs) by transposons. About 10% of transposons are estimated to carry CRMs, which may drive species-specific gene expression. The two classes of genomic changes act in concert to drive mouse-specific expression of MTF2, which links POU5F1/NANOG to NOTCH signaling. We reconstructed the transition of the GRN structures as a function of time during PED. A comparison of the GRN transition processes among the three species suggested that in the bovine system, POU5F1's interacting partner SOX2 may be replaced by HMGB1 (a TF sharing the same DNA binding domain with SOX2), resulting in rewiring of GRN by a trans change.

Evolution of the mammalian embryonic pluripotency gene regulatory network

“…Research in the mouse and other mammals has identified the main factors and signals involved in embryonic pluripotency, but we still have little insight into how deeply conserved the EP-GRN is and how it appeared during evolution. Recent studies in nonmammalian vertebrates argue for conservation of pluripotency and its genetic control (6, 7), whereas comparative genome-wide studies be- tween different mammals point to a high degree of plasticity of the EP-GRN (37,38). Our results comparing mouse and chick help clarify this apparent contradiction, because they show that, although core pluripotency factors are present in other vertebrates, the way they are connected in the EP-GRN is unique to mammals.…”

Simultaneous deletion of the methylcytosine oxidases Tet1 and Tet3 increases transcriptome variability in early embryogenesis

“…For each observed outcome, the relative contributions of oxi-mC production and DNA demethylation may be distinguished by comparing cells deficient in DNA methyltransferases, which would be depleted for both 5mC and oxi-mC, with cells deficient in TET proteins, which lack only oxi-mC. Specific downstream mechanisms include altered recruitment of key transcription factors to their binding sites in DNA, either through direct modification of the binding sequences, modulation of chromatin accessibility, or both; retrotransposon modification and expression, because insertion of these elements is known to create alternative promoters for host genes during early embryogenesis (70,71); and changes in local histone modifications, as suggested by an early study in which DNA methylation in the gene body was shown to regulate Pol II elongation efficiency through H3K4-di/tri methylation and H3K9/14 acetylation (72). Future studies will clarify these points.…”

Increased apoptosis in bovine blastocysts exposed to high levels of IGF1 is not associated with downregulation of the IGF1 receptor

“…A cross-species microarray hybridisation study revealed that gene expression profiles in bovine and human blastocysts were to a large extent identical (Adjaye et al 2007). Similarly, the transcription profiles during maternal-zygotic transition are similar between the two species (Xie et al 2010). Furthermore, the amino acid sequence of bovine IGF1 is identical to that of human IGF1 (Honegger & Humbel 1986, Francis et al 1988.…”