Nav: Home

Scientists surmount epigenetic barriers to cloning with two-pronged approach

July 19, 2018

An international group of researchers have raised the viability of mice that were cloned using a method called somatic cell nuclear transfer, by stimulating two epigenetic factors, and by doing this have shown that creating cloned animals more efficiently will require further work in the area of epigenetics. They have also uncovered a key epigenetic mechanism that appears to be a major impediment to the development of the fetus after implantation.

Cloned animals like Dolly the sheep are created through a process called somatic cell nuclear transfer (SCNT), where the nucleus of a normal body cell, which contains the DNA of an individual, is transplanted into an egg cell that has been reprogrammed into a totipotent cell. If all goes well, a genetically identical clone of the donating individual is created, but things do not usually go well. For example, in the case of Dolly, the procedure had to be carried out manually more than 277 times before the first fetus was successfully brought to term.

Recently, research groups including RIKEN scientists have concluded that epigenetic factors--changes to the chemical modifications of DNA or histone proteins rather than to the genetic code itself--play a key role in hampering the proper development of the clones. First, an epigenetic factor called histone H3 lysine 9 trimethylation has been found to be a significant barrier to proper development of the reprogrammed SCNT embryos, and removal of this factor by the injection of a demethylation factor called Kdm4d improves the rate of successful implantation of the cloned embryos. And secondly, an RNA called Xist, which normally is only expressed from the paternal X chromosome, is expressed from both X chromosomes in SCNT, leading to problems in development after implantation. As a result of these two barriers, only about one percent of SCNT embryos in mice are successfully brought to term.

For the current experiment, published in Cell Stem Cell, the researchers combined the two approaches, by using cells where the Xist gene was knocked out, and then injecting Kdm4d messenger RNA. With this combined approach, about 20 percent of the implanted cells were brought to term. The work also revealed that even when embryos implanted successfully, they often had abnormalities that prevented them from developing normally, and that there were abnormalities in the placenta itself. Further studies revealed that though the general level of epigenetic marks was similar in fertilized embryos and SCNT embryos, there were differences in the specific genes that were silenced through methylation. In addition, the scientists also discovered a specific set of genes that were not expressed from the maternal chromosome in fertilized embryos were expressed from both the paternal and maternal chromosomes in SCNT embryos. These genes are known to be involved in the development of the fetus and placenta, providing a likely explanation for the failure of development after implantation. .

According to Shogo Matoba of the RIKEN BioResource Research Center, the first author of the study, "With this work, we have definitively shown that epigenetic modifications will need to be modulated to further improve the efficiency of SCNT. We have made good progress, and have also identified a key set of genes that, we believe, impedes the proper development of the fetus after implantation. We will continue studies to find ways to overcome this further barrier, hopefully leading to even better efficiency of cloning."
-end-
The work was done in collaboration with Harvard Medical School, Zhejiang University, and other international collaborators.

RIKEN

Related Genes Articles:

Insomnia genes found
An international team of researchers has found, for the first time, seven risk genes for insomnia.
Genes affecting our communication skills relate to genes for psychiatric disorder
By screening thousands of individuals, an international team led by researchers of the Max Planck Institute for Psycholinguistics, the University of Bristol, the Broad Institute and the iPSYCH consortium has provided new insights into the relationship between genes that confer risk for autism or schizophrenia and genes that influence our ability to communicate during the course of development.
The fate of Neanderthal genes
The Neanderthals disappeared about 30,000 years ago, but little pieces of them live on in the form of DNA sequences scattered through the modern human genome.
Face shape is in the genes
Many of the characteristics that make up a person's face, such as nose size and face width, stem from specific genetic variations, reports John Shaffer of the University of Pittsburgh in Pennsylvania, and colleagues, in a study published on Aug.
Study finds hundreds of genes and genetic codes that regulate genes tied to alcoholism
Using rats carefully bred to either drink large amounts of alcohol or to spurn it, researchers at Indiana and Purdue universities have identified hundreds of genes that appear to play a role in increasing the desire to drink alcohol.
Reading between the genes
For a long time dismissed as 'junk DNA,' we now know that also the regions between the genes fulfill vital functions.
The silence of the genes
Research led by Dr. Keiji Tanimoto from the University of Tsukuba, Japan, has brought us closer to understanding the mechanisms underlying the phenomenon of genomic imprinting.
Why some genes are highly expressed
The DNA in our cells is folded into millions of small packets, like beads on a string, allowing our two-meter linear DNA genomes to fit into a nucleus of only about 0.01 mm in diameter.
Activating genes on demand
A new approach developed by Harvard geneticist George Church, Ph.D., can help uncover how tandem gene circuits dictate life processes, such as the healthy development of tissue or the triggering of a particular disease, and can also be used for directing precision stem cell differentiation for regenerative medicine and growing organ transplants.
Controlling genes with light
Researchers at Duke University have demonstrated a new way to activate genes with light, allowing precisely controlled and targeted genetic studies and applications.

Related Genes Reading:

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Digital Manipulation
Technology has reshaped our lives in amazing ways. But at what cost? This hour, TED speakers reveal how what we see, read, believe — even how we vote — can be manipulated by the technology we use. Guests include journalist Carole Cadwalladr, consumer advocate Finn Myrstad, writer and marketing professor Scott Galloway, behavioral designer Nir Eyal, and computer graphics researcher Doug Roble.
Now Playing: Science for the People

#529 Do You Really Want to Find Out Who's Your Daddy?
At least some of you by now have probably spit into a tube and mailed it off to find out who your closest relatives are, where you might be from, and what terrible diseases might await you. But what exactly did you find out? And what did you give away? In this live panel at Awesome Con we bring in science writer Tina Saey to talk about all her DNA testing, and bioethicist Debra Mathews, to determine whether Tina should have done it at all. Related links: What FamilyTreeDNA sharing genetic data with police means for you Crime solvers embraced...