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Zhang Lab Highlights

January 5, 2016

Dr. Minchul Kim was awarded National Research Service Award (F32) by the NIH

Dr. Kim will investigate molecular mechanisms of totipotency,  a transient developmental state which possesses the ability to differentiate into both placental and embryonic tissues. Using the phenomenon that cultured embryonic stem cell includes subpopulation of totipotent cells together with CRISPR-Cas9 technology, Minchul plans to perform unbiased screening to identify regulators of totipotency. Identified factors will be studied in detail through epigenomic approaches and in vitro fertilization. Results of this study will have significant impact in both basic developmental biology and regenerative medicine.  

November 4, 2015

Improved cell cloning technique makes the jump from mice to humans

By Tom Ulrich

Roughly a year ago we told you about Yi Zhang, PhD - a stem cell biologist in Boston Children's Hospital's Program in Cellular and Molecular Medicine - and his efforts to make a cloning technique called somatic cell nuclear transfer (SCNT) more efficient.

With SCNT, researchers take an egg cell and replace its nucleus with that of an adult cell (such as a skin cell) from another individual. The donated nucleus basically reboots an embryonic state, creating a clone of the original cell.

It's a hot topic in both agriculture and regenerative medicine. SCNT-generated cells can be used to clone an animal (remember Dolly the sheep?) or produce embryonic stem (ES) cell lines for research. But it's an inefficient process, producing very few animal clones or ES lines for the effort and material it takes.

Zhang's team reported last year that they could boost SCNT's efficiency significantly by removing an epigenetic roadblock that kept embryonic genes in the donated nucleus from activating in cloned cells. Now, in a new paper in Cell Stem Cell, Zhang and his collaborators report that they've extended their work to improve the efficiency of SCNT in human cells.

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November 5, 2014

Removing roadblocks to therapeutic cloning to produce stem cells

By: Tom Ulrich

We all remember Dolly the sheep, the first mammal to be born through a cloning technique called somatic cell nuclear transfer (SCNT). As with the thousands of other SCNT-cloned animals ranging from mice to mules, researchers created Dolly by using the nucleus from a grown animal’s cell to replace the nucleus of an egg cell from the same species.

The idea behind SCNT is that the egg’s cellular environment kicks the transferred nucleus’s genome into an embryonic state, giving rise to an animal genetically identical to the nucleus donor. SCNT is also a technique for generating embryonic stem cells for research purposes.

While researchers have accomplished SCNT in many animal species, it could work better than it does now. It took the scientists who cloned Dolly 277 tries before they got it right. To this day, SCNT efficiency—that is, the percent of nuclear transfers it takes generate a living animal—still hovers around 1 to 2 percent for mice, 5 to 20 percent in cows and 1 to 5 percent in other species. By comparison, the success rate in mice of in vitro fertilization (IVF) is around 50 percent.

“The efficiency is very low,” says Yi Zhang, PhD, a stem cell biologist in Boston Children’s Hospital’s Program in Cellular and Molecular Medicine. “This indicates that there are some barriers preventing successful cloning. Thus our first goal was to identify such barriers.”

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December 5, 2013

Study identifies protein that helps developing germ cells wipe genes clean of past imprints

By: Tom Ulrich

A protein called Tet1 is partly responsible for giving primordial germ cells a clean epigenetic slate before developing into sperm and egg cells, according to a new study by researchers at Boston Children's Hospital. This discovery could help provide clues to the cause of some kinds of neonatal growth defects and may also help advance the development of stem cell models of disease.

The findings were reported online Dec. 1 in Nature by a research team led by Yi Zhang, PhD, and Shinpei Yamaguchi, PhD, of Boston Children's Program in Cellular and Molecular Medicine.

Each of our cells carries two copies, or alleles, of every gene in our genome, one from each parent. In certain genes, one allele is imprinted—marked with small chemical tags called methyl groups—to keep it silent and prevent biological conflicts from arising between the two copies.

Before they mature into sperm or egg cells, primordial germ cells' imprinting patterns are erased and then re-established in an allele-specific manner. This process ensures that in the developing embryo only one member of each pair of alleles is expressed.

Zhang and Yamaguchi showed in a mouse model lacking the Tet1 gen

e that loss of the Tet1 protein prevented primordial germ cells from erasing their imprints, leading to embryonic lethality and reductions in the size of live-born offspring. The results suggest that Tet1 mutations may contribute to certain human birth defects and also provide insight into the mechanisms underlying the erasure process.

"We've long known what proteins are responsible for establishing imprinting patterns," says Zhang. "How erasure occurs has been less clear.

"We realize that Tet1 does not act alone in the erasure of genomic imprints, but is one important factor," he added. "We need to do additional work to understand what other proteins are involved."

Zhang noted that proper imprinting also has a role in cellular reprogramming, such as the generation of induced pluripotent stem (iPS) cells.

"Proper imprinting pattern is critical for the maintenance of normal development and differentiation, but abnormal imprinting pattern is frequently observed in iPS cells after reprogramming,” he explained. "Understanding how imprints are erased could lead to more effective methods of high-quality iPS cell generation."

The study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (grant number U01DK089565), the Japan Society for the Promotion of Science and the Howard Hughes Medical Institute.

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