New insights in the epigenome of embryonic stem cells

Marks, Hendrik

In naive embryonic stem cells not all genes are active, as previously thought. Rather these genes are "paused" by RNA Polymerase II at their promoters. These findings were made at the Radboud University Nijmegen (the Netherlands) in collaboration with the team of Austin Smith in Cambridge. The results were published in Cell April 27th.

Embryonic stem cells (ES cells) are special and valuable cells. ES cells are isolated from very early embryonic stages and are a model system for embryonic development. ES cells are able to divide and multiply continuously ("self-renewal") and have the capacity to specialize ("pluripotency"). They are able to differentiate into any specific cell-type of the body, including cells for organs, muscle, bone and blood. Due to these unique properties, expectations for the use of ES cells in the clinic are high.

Modern ES cell culturing techniques reveal new insights

However, it is very challenging to culture the ES cells outside of the body (invitro). For most organisms it's actually not (yet) possible at all to grow ES cells invitro. For those organisms for which it is possible, the ES cells are often different from the actual cells in the body itself. This complicates research and makes the interpretation of the molecular findings in ES cells difficult. A new culturing method, developed by the professor Austin Smith at the Welcome Trust Stem Cell Institute in Cambridge (UK) largely solves these problems. This leads to new insights.

A team of professor Henk Stunnenberg collaborated with Austin Smith to discover to their surprise that in naive mouse embryonic stem cells the oncogene c-myc, considered to be an essential gene for cell division and proliferation, was almost absent; there were less genes active than expected; there is hardly any inhibition on inactive genes; a lot of genes seem to be "on hold". From this state, the ES cells can efficiently differentiate.

The Opposite: Genes are selectively turned on, not off

'This research gives new insights in mechanisms in ES cells to remain ES cells, but also to be able to become specialized cells. One of the dogmas in our field of research has been that it was important for ES cells to have all genes active (albeit often to a low level). ES cells would subsequently differentiate by turning genes off that are not relevant for a specific specialisation, to finally reach the correct combination of active genes for a particular specialisation', Hendrik Marks, the first author of the study, explains. 'We now see the opposite: Genes are selectively turned on. However, the epigenome, the proteins present on the genome that instruct how, when and where genes should be activated, is already prepared for action. RNA Polymerase, the enzyme that transcribes the genes and thus produces the RNA, is prepared at the start of the genes. It only needs a signal to start doing its job. Moreover, the levels of the inhibiting H3K27me3 on the genes are low. That saves an additional step for the activation of the gene: the inhibiting methylgroup does not have to be removed from the histones before activation of the genes.

Epigenetic Experts

Marks is part of the team of professor Henk Stunnenberg, worldwide one of the leading experts in the field of epigenetics. The research leading to these findings was supported by a large collaborative consortium ("HEROIC") supported by the European Union. This consortium, headed by prof Stunnenberg, aimed at identifying epigenetic mechanisms in mouse ES cells.

Hendrik Marks, Tüzer Kalkan, Roberta Menafra, Sergey Denissov, Kenneth Jones, Helmut Hofemeister, Jennifer Nichols, Andrea Kranz, A. Francis Stewart, Austin Smith, and Hendrik G. Stunnenberg. The Transcriptional and Epigenomic Foundations of Ground State Pluripotency. Cell. 2012, April 27th.

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