Rewiring stem cells

sc604 — Thu, 09 Jan 2014 17:00:00 +0000

A fast and comprehensive method for determining the function of genes could greatly improve our understanding of a wide range of diseases and conditions, such as heart disease, liver disease and cancer.

̽��ֱ��method uses stem cells with a single set of chromosomes, instead of the two sets found in most cells, to reveal what causes the “circuitry” of stem cells to be rewired as they begin the process of conversion into other cell types. ̽��ֱ��same method could also be used to understand a range of biological processes.

Embryonic stem cells rely on a particular gene circuitry to retain their original, undifferentiated state, making them self-renewing. ̽��ֱ��dismantling of this circuitry is what allows stem cells to start converting into other types of cells - a process known as cell differentiation - but how this happens is poorly understood.

Researchers from the ̽��ֱ�� of Cambridge Wellcome Trust-Medical Research Council Stem Cell Institute have developed a technique which can pinpoint the factors which drive cell differentiation, including many that were previously unidentified. ̽��ֱ��method, outlined in the Thursday (9 January) edition of the journal Cell Stem Cell, uses stem cells with a single set of chromosomes to uncover how cell differentiation works.

Cells in mammals contain two sets of chromosomes – one set inherited from the mother and one from the father. This can present a challenge when studying the function of genes, however: as each cell contains two copies of each gene, determining the link between a genetic change and its physical effect, or phenotype, is immensely complex.

“ ̽��ֱ��conventional approach is to work gene by gene, and in the past people would have spent most of their careers looking at one mutation or one gene,” said Dr Martin Leeb, who led the research, in collaboration with Professor Austin Smith. “Today, the process is a bit faster, but it’s still a methodical gene by gene approach because when you have an organism with two sets of chromosomes that’s really the only way you can go.”

Dr Leeb used unfertilised mouse eggs to generate embryonic stem cells with a single set of chromosomes, known as haploid stem cells. These haploid cells show all of the same characteristics as stem cells with two sets of chromosomes, and retain the same full developmental potential, making them a powerful tool for determining how the genetic circuitry of mammalian development functions.

̽��ֱ��researchers used transposons – “jumping genes”– to make mutations in nearly all genes. ̽��ֱ��effect of a mutation can be seen immediately in haploid cells because there is no second gene copy. Additionally, since embryonic stem cells can convert into almost any cell type, the haploid stem cells can be used to investigate any number of conditions in any number of cell types. Mutations with important biological effects can then rapidly be traced to individual genes by next generation DNA sequencing.

“This is a powerful and revolutionary new tool for discovering how gene circuits operate,” said Dr Leeb. “ ̽��ֱ��cells and the methodology we’ve developed could be applied to a huge range of biological questions.”

For more information on this story, contact Sarah Collins on sarah.collins@admin.cam.ac.uk.

A new technique for determining what causes stem cells to convert into other cell types could revolutionise our understanding of how genes function.

̽��ֱ��cells and the methodology we’ve developed could be applied to a huge range of biological questions.

Martin Leeb

Chromosomes in haploid mouse embryonic stem cells

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Scientists create mammalian cells with single chromosome set

gm349 — Tue, 13 Sep 2011 15:15:32 +0000

Cambridge researchers have created mammalian cells containing a single set of chromosomes for the first time in research funded by the Wellcome Trust and EMBO. ̽��ֱ��technique should allow scientists to better establish the relationships between genes and their function.

Mammal cells usually contain two sets of chromosomes – one set inherited from the mother, one from the father. ̽��ֱ��genetic information contained in these chromosome sets helps determine how our bodies develop. Changes in this genetic code can lead to or increase the risk of developing disease.

To understand how our genes function, scientists manipulate the genes in animal models – such as the fruit fly, zebrafish and mice – and observe the effects of these changes. However, as each cell contains two copies of each chromosome, determining the link between a genetic change and its physical effect – or ‘phenotype’ – is immensely complex.

Now, in research published last week in the journal Nature, Drs Anton Wutz and Martin Leeb from the Wellcome Trust Centre for Stem Cell Research at the ̽��ֱ�� of Cambridge report a technique which enables them to create stem cells containing just a single set of chromosomes from an unfertilised mouse egg cell. ̽��ֱ��stem cells can be used to identify mutations in genes that affect the cells' behaviour in culture. In an additional step, the cells can potentially be implanted into the mouse for studying the change in organs and tissues.

̽��ֱ��technique has previously been used in zebrafish, but this is the first time it has been successfully used to generate such mammalian stem cells.

Dr Wutz, a Wellcome Trust Senior Research Fellowship, explains: “These embryonic stem cells are much simpler than normal embryonic mammalian stem cells. Any genetic change we introduce to the single set of chromosomes will have an easy-to-determine effect. This will be useful for exploring in a systematic way the signalling mechanisms within cell and how networks of genes regulate development.”

̽��ֱ��researchers hope that this technique will help advance mammalian genetics and our understanding of the gene-function relationship in the same way that a similar technique has helped geneticists understand the simpler zebrafish animal model.

Understanding how our genetic make-up functions and how this knowledge can be applied to improve our health is one of the key strategic challenges set out by the Wellcome Trust. Commenting on this new study, Dr Michael Dunn, Head of Molecular and Physiological Sciences at the Wellcome Trust, says:

“This technique will help scientists overcome some of the significant barriers that have so far made studying the functions of genes so difficult. This is often the first step towards understanding why mutations lead to disease and, ultimately, to developing new drugs treatments.”

Researchers have created mammalian cells containing a single set of chromosomes instead of two.

These embryonic stem cells are much simpler than normal embryonic mammalian stem cells. Any genetic change we introduce to the single set of chromosomes will have an easy-to-determine effect. This will be useful for exploring in a systematic way the signalling mechanisms within cell and how networks of genes regulate development.

Dr Wutz, a Wellcome Trust Senior Research Fellowship, explains

Image Anton Wutz

Partial view of haploid chromosome set

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̽��ֱ�� of Cambridge - Martin Leeb

Rewiring stem cells

Scientists create mammalian cells with single chromosome set