Scientists have identified about two dozen genes that control embryonic stem cell fate.  The genes may either prod or restrain stem cells from drifting into a kind of limbo, they suspect.  The limbo lies between the embryonic stage and fully differentiated, or specialized, cells, such as bone, muscle or fat.

By knowing the genes and proteins that control a cell’s progress toward the differentiated form, researchers may be able to accelerate the process – a potential boon for the use of stem cells in therapy or the study of some degenerative diseases, the scientists say.

Their finding comes from the first large-scale search for genes crucial to embryonic stem cells.  The research was carried out by a team at the University of California, San Francisco and is reported in a paper in the July 11, 2008 issue of “Cell.”

“The genes we identified are necessary for embryonic stem cells to maintain a memory of who they are,” says Barbara Panning, PhD, associate professor of biochemistry and biophysics at UCSF, and senior author on the paper.  “Without them the cell doesn’t know whether it should remain a stem cell or differentiate into a specialized cell.”

The scientists used a powerful technique known as RNA interference, or RNAi, to screen more than 1,000 genes for their role in mouse embryonic stem cells.  The technique allows researchers to “knock down” individual genes, reducing their abundance in order to determine the gene’s normal role.

The research focused on proteins that help package DNA.  In the nucleus, DNA normally wraps around protein complexes called nucleosomes, forming a structure known as chromatin.  This is what makes up chromosomes.

They found 22 proteins, each of which is essential for embryonic stem cells to maintain their consistent shape, growth properties, and pattern of gene expression.

Most of the genes code for multi-protein complexes that physically rearrange, or “remodel” nucleosomes, changing the likelihood that the underlying genes will be expressed to make proteins.

The main player they identified is a 17-protein complex called Tip60-p400.  This complex is necessary for the cellular memory that maintains embryonic stem cell identity, Panning explains.  Without it, the embryonic stem cells turned into a different cell type, which had some features of a stem cell but many features of a differentiated cell.

The scientists believe that Tip60-p400 is necessary for embryonic stem cells to correctly read the signals that determine cell type.  These findings are not only important for understanding cellular memory in embryonic stem cells, but will also likely be relevant to other cell types, they say.

Inactivation of other genes disrupted embryonic stem cell proliferation.  These genes were already known to have only slight influence on viability of mature cells in the body.  This suggests that embryonic stem cells are “uniquely sensitive to certain perturbations of chromatin structure,” the scientists report.

If other types of stem cells are also found to be sensitive to these chromatin perturbations, this could lead to novel cancer therapies in the future, Panning says.

Prenatal biochemical screening tests are widely used to look for chromosomal abnormalities in the fetus which can lead to serious handicap, or even death during gestation or in the first few days after birth. But these tests are only able to detect fewer than half of the total chromosomal abnormalities in the fetus, a scientist will tell the annual conference of the European Society of Human Genetics tomorrow (Monday 2 June) Dr. Francesca R. Grati, of the TOMA Laboratory, Busto Arsizio, Italy, says that these findings mean that women should be better informed on the limitations of such diagnostic tests.The researchers studied 115,576 prenatal diagnoses carried out during the last fourteen years. 84,847 were amniocenteses, usually carried out around the 16th week of pregnancy, and 30,729 chorionic villus samplings, which can be undertaken from 12 weeks into the pregnancy. Both these tests carry an increased risk of miscarriage, so the decision on whether or not to undertake them can be difficult to weigh up. “Since our sample included a large number of women aged less than 35 who underwent invasive prenatal diagnosis without any pathological indication to do so, we felt that the results could be useful in helping to inform pre-test counselling of such women”, says Dr. Grati. “Up until now, the information we had came from smaller studies which only looked at the performance of these tests in detecting a limited number of chromosomal abnormalities.”

After analysing the results of the chromosomal abnormalities from their own dataset, the researchers combined them with the official detection rates for these abnormalities published by SURUSS and FASTER consortia. These are multi-centre research groups involved in the investigation of screening and diagnostic tests performed in pregnancy, whose results are being used to optimise prenatal care for pregnant patients. They found that current screening procedures were only able to detect half the total chromosomal abnormalities in women both younger and older than 35.

The TOMA laboratory is particularly suited to carry out this kind of research, says Dr. Grati, because it was among the first in the world to deal with prenatal diagnosis, and has a vast number of prenatal diagnostic samples at its disposal.

Current tests do not detect all fetal chromosomal abnormalities, but only trisomies 21 (Down syndrome), 18 (Edward’s syndrome), and 13 (Patau syndrome), monosomy X (Turner syndrome), and triploids (conceptuses with 69 chromosomes instead of 46). “These are common vital chromosomal abnormalities, but there are many others which are not picked up by these tests”, says Dr. Grati. “And the tests do not even detect 100% of the common abnormalities.”

At conception, 23 chromosomes from each parent combine to create a fetus with 46 chromosomes in all its cells. Trisomy occurs when the fetus has one additional chromosome (47 instead 46). The extra genetic material from the additional chromosome causes a range of problems of varying severity.

In Down syndrome, for example, where the fetus has three copies of chromosome 21, babies are usually born with impaired cognitive ability and physical growth, cardiac defects and a characteristic facial appearance. Unlike many other such abnormalities, however, babies born with Down syndrome are able to lead relatively normal lives and their life expectancy is around 50 years.

Other than trisomy, the fetus can also have the loss of genetic material (deletions) or chromosomal abnormalities in a non-homogeneous form, where there is a mixture of two cell lines, one normal and the other abnormal. “Some of these disorders are relatively common in the fetus, which may have as much chance of surviving as children who are born with Down syndrome, and it is worrying that current biochemical tests are not always able to detect them” says Dr. Grati. “Our research confirms that it is fundamental for doctors to counsel patients about the limitations of current screening methods, so that they can make an informed decision on whether or not to undergo invasive diagnostic testing.”