Molecular determinants critical for pluripotent cell fate found

Researchers at the Centre for Genomic Regulation (CRG) have uncovered new molecular determinants that underlie how pluripotent cells, which can differentiate into any type of cell in the body, decide their destiny. The research, published today in the journal Molecular Cell, provides new insights into early embryo development and new clues for understanding cancer. The work was led by Ramon y Cajal researcher Dr. Sergi Aranda and ICREA Research professor Dr. Luciano Di Croce.

Using embryonic stem cells from mice, the researchers found that the enzyme Thymine DNA Glycosylase (TDG) is critical for cell differentiation. They observed that TDG levels fluctuate as part of the cell's normal routine. When the cell is preparing to divide, TDG levels are high, but they drop off once the cell enters the division phase.

Temporarily altering TDG levels also changed the way stem cells differentiate, or turn into different types of cells. For example, stem cells with tweaked TDG levels had an increased tendency to turn into heart muscle cells. This suggests that the starting amount of TDG in pluripotent cells can affect what type of cells they become when they differentiate.

One of the surprising findings the researchers made is that TDG mainly interacts with p53, a well-known tumour suppressor. The p53 gene is one of the most frequently mutated genes in human cancers, with around half of all human tumors containing a mutation or deletion in the gene.

The researchers found that TDG works by facilitating p53's chromatin recruitment, effectively controlling the p53 transcriptional response in a cell cycle-dependent manner. This regulation was pivotal for cell fate decisions during differentiation from pluripotency.

Cancer is a common disease caused by problems in cell fate decision-making. When the processes that control cell growth, differentiation, and death are disrupted, cells may proliferate uncontrollably, fail to differentiate into their intended cell types, or refuse to die when they should, all of which contribute to the development and progression of the disease.

While further work is needed to explore TDG’s exact role in cancer, the present study could open up new avenues for investigating the molecular mechanisms behind cancer development, which could eventually lead to new diagnostic and therapeutic strategies.

“We believe that our study can offer fresh insights into how cells determine their fate and how temporary changes can lead to altered cell behavior. These findings could have important implications for human health, especially considering that p53 is the most commonly mutated gene in cancer,” says Dr. Sergi Aranda.

Image: Mouse embryonic stem cells, used in the study. Credit: Sergi Aranda/CRG

Reference work: Aranda S.; Alcaine-Colet A.; Ballaré C.; Blanco E.; Mocavini I.; Sparavier A.; Vizán, P.; Borràs E.; Sabidó E.; Di Croce L. Thymine DNA glycosylase regulates cell cycle-driven p53 transcriptional control in pluripotent cells. Molecular Cell, in press; https://doi.org/10.1016/j.molcel.2023.07.003