Systems based analysis of human embryos and gene networks involved in cell lineage allocation

Abstract

Background Little is understood of the molecular mechanisms involved in the earliest cell fate decision in human development, leading to the establishment of the trophectoderm (TE) and inner cell mass (ICM) stem cell population. Notably, there is a lack of understanding of how transcriptional networks arise during reorganisation of the embryonic genome post-fertilisation. Results We identified a hierarchical structure of preimplantation gene network modules around the time of embryonic genome activation (EGA). Using network models along with eukaryotic initiation factor (EIF) and epigenetic-associated gene expression we defined two sets of blastomeres that exhibited diverging tendencies towards ICM or TE. Analysis of the developmental networks demonstrated stage specific EIF expression and revealed that histone modifications may be an important epigenetic regulatory mechanism in preimplantation human embryos. Comparison to published RNAseq data confirmed that during EGA the individual 8-cell blastomeres are transcriptionally primed for the first lineage decision in development towards ICM or TE. Conclusions Using multiple systems biology approaches to compare developmental stages in the early human embryo with single cell transcript data from blastomeres, we have shown that blastomeres considered to be totipotent are not transcriptionally equivalent. Furthermore we have linked the developmental interactome to individual blastomeres and to later cell lineage. This has clinical implications for understanding the impact of fertility treatments and developmental programming of long term health. Electronic supplementary material The online version of this article (10.1186/s12864-019-5558-8) contains supplementary material, which is available to authorized users.

Interactome comparison of human embryonic stem cell lines with the inner cell mass and trophectoderm

“…Concern has been raised (Stirparo, et al, 2018) about the heterogeneity of tissue classification in the 373 single cell RNAseq data from Petropoulos et al (Petropoulos, et al, 2016). Our work broadly supports 374 these observations but also highlights that tissue classification can be made despite concerns in the 375 sample preparation (Stirparo, et al, 2018) or in inter individual differences (Smith, et al, 2019). This 376 observation would suggest that rigid definitions of tissue specific expression are not necessarily 377 helpful as we expand into single cell analysis.…”

“…Transcriptional analysis of isolated ICM and TE samples from individual human embryos has also been 36 performed, highlighting key metabolic and signalling pathways (Adjaye, et al, 2005). A recent study 37 of 1529 individual cells from 88 human preimplantation embryos defined a transcriptional atlas of this 38 stage of human development (Petropoulos, et al, 2016), however cell lineage allocation can be 39 problematic and inter-individual heterogeneity has been shown to have a major effect on gene 40 expression (Smith, et al, 2019;Stirparo, et al, 2018). Together these data show the relevance of 41 transcriptome based analysis and highlight the need for approaches that account for inter-individual 42…”

Small Noncoding RNA Signatures for Determining the Developmental Potential of an Embryo at the Morula Stage

“…Gene expression profiling and analysis is emerging as a promising tool to improve the understanding and, thereby, assessment of what determines the quality of the embryo. Many researchers have attempted to characterize the expression profile of protein-coding genes at different stages of early embryogenesis [ 11 , 54 , 55 ]. SncRNAs are important regulators of their expression at the transcriptional and post-transcriptional levels.…”

Ovarian Aging: Molecular Mechanisms and Medical Management

“…Moreover, even with the same genetic background, with the use of multiple systems biologic approaches to compare developmental stages in the early human embryo with single-cell transcript data from blastomeres, it was shown that blastomeres considered to be totipotent were not transcriptionally equivalent [ 22 ].…”