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Embryo gene activation events linked to cancer

In a recent paper, published in the journal Cell Reports, embryologists have discovered how genes in early embryos are switched on – and they hope this new information could eventually aid the discovery of therapeutic targets for cancer. The work is a collaborative effort between researchers at the University of Bath and the University of Cambridge, as well as colleagues in Germany and the US.

Embryonic development

In the initial period after fertilisation, the genes in an embryo are switched off. For a foetus to develop, these genes must be switched on. The onset of embryonic transcription is critical to this process, but currently very little is known about the triggers for this activation.

In order to identify gene activity at precise times post-fertilisation, Tony Perry (Professor at the Department of Life Sciences, University of Bath) and his team used high-resolution single-cell RNA sequencing to analyse one-cell embryos in mice. They found that (at least in mouse embryos) the genes kick into action within four hours of fertilisation and are activated in a pre-set order. The authors refer to this as the “program of embryonic gene expression.” This is the first time this sequence of gene activation in embryos has been identified in any species.

A new approach

The new technology, called ZFDesign, uses AI to model the interactions between DNA and the ZF domains. It also considers the influence of multiple adjacent finger environments.

Figure 1: A mouse EGA program initiates rapidly after fertilization. (A) Map plots showing DEGs relative to levels in metaphase II (mII) oocytes from microarray and F2-B6cast scRNA-seq series.(B) Multidimensional scaling (MDS) analysis of microarray data and t-SNE visualization of F2 and B6cast scRNA-seq data.(C) Relationships of microarray and scRNA-seq data across the 12-h time course.(D) Heatmap showing mouse one-cell embryo gene expression changes.(E) iEGA pathway succession and canonical embryonic events in the first 12 h.(F) Relative levels (±SEM) of MuERV transcripts LTRPol, and Gag at the times shown after fertilization, from scRNA-seq and qPCR of pools of in vitro fertilization embryos.

Besides simply identifying this gene expression program, the team also learned more about the molecular switches activating the genes. They were already aware of some of the “usual suspects” in terms of the molecular switches, and also found that the transcribed genes predicted that transcription factors (TFs) associated with cancer may regulate them – including c-Myc.

“Many factors responsible for the dawn of gene activity in embryos have long been known to be major oncogenes,” said Perry. “Quite possibly, carcinogenesis recapitulates embryogenesis.”

Cancer connection

To test whether TFs associated with cancer were driving the activation of embryo development genes, they decided to try inhibiting c-Myc. They discovered that without c-Myc activity, many of the genes were never switched on and the embryos simply stopped developing. This indicates that c-Myc is indeed a molecular finger that switches on embryo genes. The team suggests that factors such as c-Myc lay dormant in eggs until activated by the process of fertilisation.

This new model of transcription in early development provides new avenues to explore in terms of embryonic totipotency and even potential new targets for cancer therapy. “Our work could open a new clinical chapter for the early detection of cancer,” added Professor Perry.