Study Identifies Stabilization Mechanism of ‘Dnmt3L Protein’ That Determines Stem Cell Quality and Differentiation

A research team led by Professor Dong-Myung Shin of Asan Medical Center published the findings in ‘Experimental & Molecular Medicine’ (impact factor: 12.9), a sister journal of Nature.

▲ (From left) Professor Dong-Myung Shin and Research Professor Seungun Lee from the Department of Cell and Genetic Engineering, along with Professor Kyunggon Kim from the Department of Biomedical Informatics and Statistics at Asan Medical Center

Stem cells are often regarded as the key to treating incurable diseases, but their clinical application has been limited by quality deterioration during large scale culture and expansion. Recently, a Korean research team became the first in the world to identify how a key protein that determines stem cell quality is regulated, raising the possibility of developing higher quality cell therapies.

A research team led by Professor Dong-Myung Shin and Research Professor Seungun Lee from the Department of Cell and Genetic Engineering at Asan Medical Center, along with Professor Kyunggon Kim from the Department of Biomedical Informatics and Statistics at Asan Medical Center, identified the molecular mechanism by which Dnmt3L, a key protein responsible for maintaining stem cell identity and differentiation capacity, is stably regulated within cells.

The Dnmt3L protein plays a critical role in determining the quality and differentiation capacity of stem cells. However, it is highly susceptible to deterioration depending on culture conditions.

To precisely track changes in stem cell quality, the research team analyzed gene expression patterns under various culture conditions, including 2i and serum based environments. The team also employed advanced mass spectrometry techniques to examine protein level changes in protein levels at the molecular level.

The analysis revealed that epigenetic modifications known as acetylation occurred at two specific amino acid residues within the Dnmt3L protein, K238 and K412. Once acetylated, the Dnmt3L protein was no longer properly degraded and instead accumulated excessively within the cells.

To further investigate how the acetylation process is regulated, the research team conducted co immunoprecipitation (Co IP) experiments.

The results demonstrated that Prdm14 and G9a, proteins known to play essential roles in maintaining stem cell identity, directly bind to Dnmt3L to suppress acetylation and promote its degradation. These findings molecularly confirm that specific protein complexes within cells function as guardians that protect the genetic integrity of stem cells.

Beyond identifying the mechanism, the research team also verified its functional impact on stem cells. Stem cells engineered to undergo acetylation gradually lost their normal DNA methylation patterns over time, and their ability to differentiate into neural cells, cardiac cells, and other cell types declined markedly compared with normal cells.

These findings suggest that the acetylation status of Dnmt3L could serve as a critical indicator for selecting and manufacturing high quality stem cells.

Professor Dong-Myung Shin of the Department of Cell and Genetic Engineering at Asan Medical Center said, “This study is significant in that it provides an important clue for overcoming epigenetic instability and quality deterioration, longstanding challenges in stem cell culture.”

He added, “By maximizing differentiation efficiency into specific cell types such as neural, cardiac, and germ cells, this technology is expected to contribute to the large scale production of high quality personalized cell therapies and improve the safety of regenerative medicine in the future.”

The study was recently published in ‘Experimental & Molecular Medicine’ (impact factor: 12.9), a prestigious biochemistry journal and sister publication of Nature.

This research was supported by the Korea Government Wide R&D Project for Regenerative Medicine, the Mid Career Researcher Program funded by the Ministry of Science and ICT, and the Academic Research Support Program funded by the Ministry of Education. A patent application related to the technology has also been completed.