‘Second genetic code’ edited in stem cells to study disease-causing … – The San Diego Union-Tribune

Scientists led by Salk Institute researchers say they have introduced stable changes into human stem cells that control how their genes are activated or suppressed.

This first-time accomplishment in the field known as epigenetics or epigenomics will help research into diseases caused by improper activation or silencing of genes, the scientists say in a study published Thursday in Science.

Stem cell researcher Juan Carlos Izpisa Belmonte was the senior author. Yuta Takahashi, also of the Salk Institute, was the first author. The study can be found at: j.mp/cpgstem.

Epigenetics concerns chemical additions or subtractions to DNA that dont change the underlying genetic sequence. It has been called the second genetic code, because of its profound effect on how genes function.

This is a major way of having homeostasis and control and interaction with the environment, Izpisa Belmonte said. I would say its as important as the genome.

Malfunctions in the epigenetic code have been linked to cancer, Angelman syndrome and a related condition called Prader-Willi syndrome, among other diseases. In the study, epigenetic changes associated with colon cancer were reproduced, as was an epigenetic defect that causes one form of Angelman syndrome. (The syndrome is also caused by a genetic mutation or deletion).

The new study extends the Izpisa Belmonte labs recent development of a new technology to modify genes in non-dividing cells, which make up many of the cells in the human body. By introducing changes in pluripotent stem cells, researchers can also alter the epigenetic profile expressed in them and the adult cells derived from them.

Research is now in progress to test epigenetic modifications on whole animals, Izpisa Belmonte said.

Studying epigenetic alterations has been difficult because unlike genetic changes, epigenetic changes cant be stably introduced into cells.

The Salk Institute-led study demonstrated how to do this, creating stem cells that reliably pass along their modified epigenomes to descendant cells, and to mature cells produced from them.

They used a widely occurring epigenetic process called methylation, which involves adding or subtracting a methyl group. Adding a methyl group suppresses the gene.

This technology lays the underpinnings for more complete studies of how epigenetics factors into diseases, and how to treat them, Izpisa Belmonte said.

Complicated, but cool

Stem cell researcher Jeanne Loring described the studys technology as very complicated, but cool.

While we know the whole DNA sequence, we dont know very much at all about how the activity of the genome is regulated - what genes are active where, and when, Loring wrote in an email.

One of the most mysterious of these regulators is DNA methylation. A lot of the genome is kept silent by a chemical modification that puts a methyl group on one of the four bases, cytosine - and we have almost no idea about how this happens.

Belmontes group has found a way to modify what parts of the genome are methylated. This is important because some diseases, including some cancers, are clearly caused by abnormal methylation of DNA. This technology will be a great tool for figuring out how genes are regulated, which will give us an opening to understanding and treating human diseases, Loring wrote.

Producing the stable changes required inventing a method to induce methylation into important areas of DNA called CpG islands that normally resist methylation. The scientists introduced CpG-free DNA into these islands, causing the entire CpG sequence to become methylated.

The methylation persisted even after the introduced DNA was removed. And the change was stably transmitted to daughter pluripotent cells, and to adult cells produced from them.

Catching up

First author Yuta Takahashi said his team performed the research to help epigenomic research catch up to genomic research.

Previously, people have tried to modify the epigenome by adding methylation, but that is not stable, Takahashi said. Theyre not stable after differentiation of the stem cells, theyre not stable even after passaging for a few times.

In our case the modifications are quite stable. We show that even after 30 passages in culture, these marks are still there. And in the disease called Angelman syndrome, the modifications are stable after differentiating into neurons.

Also important is that the modifications were produced across a wide expanse of the CpG islands, Izpisa Belmonte said. Thats because epigenetic diseases can affect broad stretches of these islands.

Some existing drugs affect epigenetic markers, but they lack precision, Takahashi said. Drugs developed with the methylation technology employed in this study would presumably be free of side effects.

Further down the road, the ability to precisely change epigenetic markers could be useful in studying embryonic development, said Jun Wu, another co-author at the Salk Institute.

While the genome of an organism is determined when egg and sperm to form a zygote, certain genes inherited from the mother are inactivated, as well as certain genes from the father. Aberrations in this process, called imprinting can produce diseases such as Angelman and Prader-Willi syndrome, which affect genes carried on the same stretch of DNA.

Prader-Willi syndrome is caused by inactivated paternal genetic activity, or the presence of two copies of the maternal genes. In Angelman syndrome, the paternal genes are inactivated, or there are two maternal genes. A partial imprinting defect has been linked to an exceptionally mild case of Angelman syndrome.

In addition, epigenetic patterns change with development and in the aging process, Wu said.

Building live animals models with altered methylation patterns can shed light on how these processes go awry in human diseases, he said.

Other authors included Keiichiro Suzuki, Paloma Martinez Redondo, Mo Li, Hsin-Kai Liao, Min-Zu Wu, Reyna Hernndez-Bentez, Tomoaki Hishida, Maxim Nikolaievich Shokhirev, Concepcion Rodriguez Esteban and Ignacio Sancho-Martinez of the Salk Institute.

The work was funded by the NIH-National Cancer Institute (NCI), the Chapman Foundation, and The Leona M. and Harry B. Helmsley Charitable Trust, UCAM and the G. Harold and Leila Y. Mathers Charitable Foundation.

bradley.fikes@sduniontribune.com

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UPDATES:

12:10 p.m.: This article was updated with additional details.

It was originally published at 11 a.m.

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'Second genetic code' edited in stem cells to study disease-causing ... - The San Diego Union-Tribune