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A recent study published in PNAS has uncovered significant obstacles in reprogramming specialized cells, a technique necessary for regenerative medicine. Led by Professors Yosef Buganim and Howard Cedar from Hebrew University and Professor Ben Stanger from Pennsylvania University, the research focuses on understanding why cells transformed into new types often struggle to maintain their identity. At the center of the issue are DNA methylation patterns, which make it difficult for reprogrammed cells to fully adopt their new roles.
Cellular Reprogramming and DNA Methylation
Cellular reprogramming, particularly through trans-differentiation, allows scientists to convert one type of specialized cell into another, such as transforming skin cells into heart cells. This process holds great potential for treating various diseases and injuries. However, the research shows that while reprogrammed cells initially resemble their new identity, they fail to maintain it over time, limiting their use in therapies.
The team focused on DNA methylation, a biochemical modification of the DNA molecule that regulates gene expression and preserves a cell's identity. "Despite significant changes in gene expression, the reprogrammed cells are unable to fully erase their original developmental instructions. This limits their ability to fully embrace their new role," explained Buganim. In essence, these methylation patterns serve as a barrier that prevents the reprogrammed cells from completely transforming into fully functional versions of their intended cell type.
New Techniques Reveal Methylation Challenges
To better investigate the persistence of DNA methylation patterns, the researchers developed an innovative technique for tracking these changes during the cell conversion process. By examining both lab-grown cells and animal tissues, the team observed that while reprogrammed cells began to resemble their target type in appearance and function, they continued to retain the DNA methylation patterns of their original identity. This finding highlights a fundamental limitation in current reprogramming strategies—reprogrammed cells do not fully reset their DNA’s regulatory mechanisms, preventing the complete erasure of their past identities.
The study indicates that the DNA methylation signatures embedded in the regulatory regions of the genome create developmental constraints. "This discovery opens up new avenues in understanding the molecular barriers to complete cellular reprogramming," added Cedar. These methylation markers resist being reset, which ultimately compromises the long-term stability and function of the reprogrammed cells.
While the study raises important questions about how to fully reprogram cells, it also offers new directions for research. "It also brings us one step closer to figuring out how to overcome these roadblocks, which could have significant implications for future medical applications," Cedar noted. By identifying DNA methylation as a significant barrier, the study lays the groundwork for future methods aimed at overcoming these obstacles.
Original Publication
Radwan A, Eccleston J, Sabag O, et al. Transdifferentiation occurs without resetting development-specific DNA methylation, a key determinant of full-function cell identity. Proceedings of the National Academy of Sciences. 2024;121(39):e2411352121. doi:https://doi.org/10.1073/pnas.2411352121
Cellular Reprogramming and DNA Methylation
Cellular reprogramming, particularly through trans-differentiation, allows scientists to convert one type of specialized cell into another, such as transforming skin cells into heart cells. This process holds great potential for treating various diseases and injuries. However, the research shows that while reprogrammed cells initially resemble their new identity, they fail to maintain it over time, limiting their use in therapies.
The team focused on DNA methylation, a biochemical modification of the DNA molecule that regulates gene expression and preserves a cell's identity. "Despite significant changes in gene expression, the reprogrammed cells are unable to fully erase their original developmental instructions. This limits their ability to fully embrace their new role," explained Buganim. In essence, these methylation patterns serve as a barrier that prevents the reprogrammed cells from completely transforming into fully functional versions of their intended cell type.
New Techniques Reveal Methylation Challenges
To better investigate the persistence of DNA methylation patterns, the researchers developed an innovative technique for tracking these changes during the cell conversion process. By examining both lab-grown cells and animal tissues, the team observed that while reprogrammed cells began to resemble their target type in appearance and function, they continued to retain the DNA methylation patterns of their original identity. This finding highlights a fundamental limitation in current reprogramming strategies—reprogrammed cells do not fully reset their DNA’s regulatory mechanisms, preventing the complete erasure of their past identities.
The study indicates that the DNA methylation signatures embedded in the regulatory regions of the genome create developmental constraints. "This discovery opens up new avenues in understanding the molecular barriers to complete cellular reprogramming," added Cedar. These methylation markers resist being reset, which ultimately compromises the long-term stability and function of the reprogrammed cells.
While the study raises important questions about how to fully reprogram cells, it also offers new directions for research. "It also brings us one step closer to figuring out how to overcome these roadblocks, which could have significant implications for future medical applications," Cedar noted. By identifying DNA methylation as a significant barrier, the study lays the groundwork for future methods aimed at overcoming these obstacles.
Original Publication
Radwan A, Eccleston J, Sabag O, et al. Transdifferentiation occurs without resetting development-specific DNA methylation, a key determinant of full-function cell identity. Proceedings of the National Academy of Sciences. 2024;121(39):e2411352121. doi:https://doi.org/10.1073/pnas.2411352121