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Stem Cell Division (Artist’s depiction).
Image Credit: Public Domain

Come here, and be quiet!

Genes are physically held silenced in 'lock-down' within embryonic stem cells — until given the proper signal.

Research has discovered a strong gene network that keeps genes silenced during early development. In the same way people interact within one room or over thousands of miles, there are short and long-distance interactions between genes within our genome. These interactions form a three-dimensional network which monitors the genome.

Now research published in Nature Genetics [1], has found how key genes unlock an embryo's blueprint for development.

Physically clustered in the nucleus of embryonic stem cells, developmental genes are kept in a silent or "locked down" state.

The different cell types which form an embryo are all derived from embryonic stem cells (ESCs). ESCs are self-renewing and remain in an undifferentiated state with the potential to become any cell type in the body. But in order to become differentiated, ESCs must lose their stem cell characteristics at the gene level. They can only become specialised after being switched on by the appropriate developmental gene signals.

Using a novel technique called "Promoter Capture Hi-C", developed at the Babraham Institute, researchers have identified an unusually strong 3D network of developmental genes in ESCs. These genes encode proteins that establish the embryo's body plan and direct organ development. To prevent ESCs from being "turned on" at the wrong time, their genes are clustered tightly together, therefore unable to be "read", "turned on" or "expressed"— thus silenced.

Researchers found that at the heart of the ESC repressed state is a protein complex called the Polycomb repressive complex (PRC1) [2]— a master regulator of ESC genome architecture. PRC1 ensures ESCs remain undifferentiated.

Babraham scientists propose that the selective release of genes from the PRC1 network leads to ESCs being expressed. Thus the PRC1 network controls early developmental decisions which define cell types. However, de-regulation of Polycomb complexes has been known to trigger several cancers and developmental disorders. Therefore, understanding exactly how Polycomb-mediated gene repression works is critical to promoting proper development.

"Analysing the genome-wide connections of 22,225 promoters in the genome of mouse embryonic stem cells [ESCs] allowed us to identify a sub-set of nearly 100 promoters which form the strongest interaction network seen in the entire genome.

"This is exciting because the members of this sub-set encode early developmental regulators which define what the embryonic stem cell will become.

"This research uncovers a mechanism for how inappropriate expression of developmental genes is prevented and also suggests how genes are freed from silencing in order for normal embryonic development to proceed."

Sarah Elderkin PhD, Group Leader, Nuclear Dynamics, Babraham Institute research program, and lead author.

Abstract [1]
"Polycomb repressive complex PRC1 spatially constrains the mouse embryonic stem cell genome"
The Polycomb repressive complexes PRC1 and PRC2 maintain embryonic stem cell (ESC) pluripotency by silencing lineage-specifying developmental regulator genes1. Emerging evidence suggests that Polycomb complexes act through controlling spatial genome organization2, 3, 4, 5, 6, 7, 8, 9. We show that PRC1 functions as a master regulator of mouse ESC genome architecture by organizing genes in three-dimensional interaction networks. The strongest spatial network is composed of the four Hox gene clusters and early developmental transcription factor genes, the majority of which contact poised enhancers. Removal of Polycomb repression leads to disruption of promoter-promoter contacts in the Hox gene network. In contrast, promoter-enhancer contacts are maintained in the absence of Polycomb repression, with accompanying widespread acquisition of active chromatin signatures at network enhancers and pronounced transcriptional upregulation of network genes. Thus, PRC1 physically constrains developmental transcription factor genes and their enhancers in a silenced but poised spatial network. We propose that the selective release of genes from this spatial network underlies cell fate specification during early embryonic development.

Abstract [2]
"Mapping long-range promoter contacts in human cells with high-resolution capture Hi-C"
Transcriptional control in large genomes often requires looping interactions between distal DNA elements, such as enhancers and target promoters. Current chromosome conformation capture techniques do not offer sufficiently high resolution to interrogate these regulatory interactions on a genomic scale. Here we use Capture Hi-C (CHi-C), an adapted genome conformation assay, to examine the long-range interactions of almost 22,000 promoters in 2 human blood cell types. We identify over 1.6 million shared and cell type–restricted interactions spanning hundreds of kilobases between promoters and distal loci. Transcriptionally active genes contact enhancer-like elements, whereas transcriptionally inactive genes interact with previously uncharacterized elements marked by repressive features that may act as long-range silencers. Finally, we show that interacting loci are enriched for disease-associated SNPs, suggesting how distal mutations may disrupt the regulation of relevant genes. This study provides new insights and accessible tools to dissect the regulatory interactions that underlie normal and aberrant gene regulation.

Funding support for this research was provided by the Wellcome Trust to Dr Sarah Elderkin, Medical Research Council (MRC) to Dr Peter Fraser and the European Commission to Dr Nicholas Luscombe as part of the FP7 EpiGeneSys Network of Excellence. The Babraham Institute is strategically funded by the Biotechnology and Biological Sciences Research Council (BBSRC).

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