Parent-Specific Stem Cells Provide Insight into Human Development

The Context: Humans inherit two sets of genes, one from each biological parent. Some of these genes have only one parent’s copy activated, while the other copy is silenced. These genes, called imprinted genes, play a significant role in normal human development, and defects in imprinted genes have been implicated in developmental syndromes like Prader-Willi syndrome and cancer. 

The Study: Researchers have created human embryonic stem cells that contain DNA from only one parent: a father or mother. These cells helped the researchers identify new imprinted genes (including some implicated in Prader-Willi Syndrome) and further illuminated the role of imprinted genes in human development. The study appears in Cell Stem Cell and was led by NYSCF – Robertson Investigator and NYSCF Research Institute Alumnus Dr. Dieter Egli and his team at Columbia University in collaboration with researchers from the NYSCF Research Institute and the Hebrew University of Jerusalem.

The Importance: This study creates a more detailed catalogue of imprinted genes and their role in healthy and abnormal human development. This information can be used to better understand developmental disease. It will also allow broader studies of human fertility and reproduction.

When we are born, we get two copies of genes: one from our father, and one from our mother. But sometimes, only one parent’s copy is active. A gene from a mother is expressed while a gene from a father is silent, or vice versa. These are called ‘imprinted genes,’ and misregulating them can lead to several developmental conditions as well as cancer.

In a new study published in Cell Stem Cell, researchers from the NYSCF Research Institute, the Hebrew University of Jerusalem, and Columbia University including NYSCF – Robertson Investigator and NYSCF Research Institute Alumnus Dieter Egli, PhD, used stem cells to identify imprinted genes and understand how they impact our development. They did so by creating embryonic stem cells carrying DNA exclusively from either egg or sperm.

Discoveries in Disease and Development

These specialized stem cells gave the researchers the power to define a new catalogue of imprinted genes, which can be used to better understand the genetics of development and disease. For example, some of the newly identified genes live in a region of the genome associated with Prader-Willi syndrome, a developmental disorder known to involve imprinting and characterized by intellectual disability, obesity, and short stature.

Embryonic stem cells can become any cell type in the body, allowing scientists to examine development of different tissues. The researchers used the parent-specific stem cells to examine how gene expression impacted the development of certain organs.

For example, the team found that cells carrying only maternal genes are better at making brain cells, and cells carrying only paternal genes are better at making liver cells. In fact, a gene called IGF2, for which only the paternal copy is normally active, is associated with Beckwith-Wiedemann syndrome, a developmental condition that can lead to an enlarged liver.

Next Steps

The stem cells will be a valuable resource for research into other diseases, including cancer. In women, human eggs that are missing DNA from a parent can form certain types of aggressive tumors, and understanding more about this process will help us develop new treatments.

“The parent-specific embryonic stem cells reported in this study can be useful to deepen our understanding of tumors affecting women,” said Susan Solomon, JD, NYSCF CEO and co-founder.

Beyond cancer, the cells will also continue to help labs understand human fertility, development, and reproduction, both in healthy and diseased individuals.

Journal Article:

Distinct Imprinting Signatures and Biased Differentiation of Human Androgenetic and Parthenogenetic Embryonic Stem Cells.
Sagi I, De Pinho JC, Zuccaro MV, Atzmon C, Golan-Lev T, Yanuka O, Prosser R, Sadowy A, Perez G, Cabral T, Glaser B, Tsang SH, Goland R, Sauer MV, Lobo R, Benvenisty N, Egli D. Cell Stem Cell. 2019. doi: 10.1016/j.stem.2019.06.013.