Researchers report proteins that accompany a key enzyme of DNA for cell differentiation

The development of an adult organism begins with a fertilized egg that differentiates into hundreds of specialized cell types including tissues and organs. The way these cellular fate changes occur is a topic of interest for research. All cells contain the same genetic information and therefore development involves the selective regulation of genes contained in DNA. The proteins that activate or deactivate these genes are called transcription factors. Similar mechanisms work when a stem cell of an adult's body, such as the blood stem cell, specializes in the types of cells needed for different functions. To ensure proper gene regulation, other types of proteins are needed, such as enzymes that alter the proteins that envelop the DNA or even the DNA itself, thus refining this complex process. It is interesting to note that alterations in these proteins due to mutations lead to aberrant gene regulation and often lead to cancer formation.

In an article published in Cell strain cell, researchers from the Center for Genomic Regulation (CRG), led by Thomas Graf, in collaboration with scientists from the Institute of Biology of the Ecole Normale Supérieure in Paris, as well as the CNAG-CRG and the Harvard Medical School, have studied this complex process. They focused their attention on an enzyme called Tet2, which plays a crucial role in the formation of pluripotent stem cells and in the differentiation of blood cells.

Tet2 is a driving force in decisions about cell fate that promotes gene expression by chemically modifying the DNA. To do this, he must bind to the DNA, but can not do it by himself. The question then arises as to what brings the Tet2 enzyme into the regions of the DNA where it does its work.

Now, Graf and his colleagues report that Tet2 is brought to the DNA by specific proteins with which it can interact. They identified three transcription factors, each of which can guide the enzyme to different sets of target genes needed to specify cell fate. Therefore, a number of different proteins can bring Tet2 into regions of the DNA where and when necessary.

"We investigated the mechanism by the actions of Tet2 by monitoring the dynamics of DNA changes during induced reprogramming of pluripotent stem cells.Our data were able to answer an open-ended question relevant not only to for the development and differentiation of embryos, but also for cell reprogramming and cancer, "says Thomas Graf, principal investigator of the study and head of the CRG group.

"Our findings will be useful to other researchers working in the treatment of leukemia and other types of cancers in which Tet2 is involved," said José Luis Sardina, first author and co-correspondent of the 39; section. "Our new data will be available to the clinical research community." This is another example of how basic research discovering the fundamental mechanisms of gene regulation could also have medical applications, in this case, in cancer and cell regeneration, "he concludes.

The study also reported another unexpected discovery, namely that transcription factors can recruit Tet2 into specific regions of the DNA without the displacement of proteins that envelop DNA, contained in the self. -describing nucleosomes. This represents a new way in which transcription factors interact with the genome, acting as pioneers for Tet2 positioning. Graf states, "It will now be fascinating to discover the role of cellular fate decisions of genome regions linked by these pioneering factors".

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More information:
Jose Luis Sardina et al., Transcription factors lead to the demethylation of the amplifier with Tet2 in order to reprogram the fate of the cells, Cell strain cell (2018). DOI: 10.1016 / j.stem.2018.08.016