News from the CRG
The development of an adult organism starts with a fertilized egg that differentiates into hundreds of specialized cell types contained in tissues and organs. How these cell fate changes happen is intensely investigated all over the world. What we know is that all our cells contain the same genetic information, therefore development involves the selective regulation of genes contained in the DNA. The proteins that turn on or off these genes are called transcription factors. Similar mechanisms operate when a stem cell in the adult body, such as the blood stem cell, specializes into cell types needed for different functions. To ensure correct gene regulation additional kinds of proteins are required, such as enzymes that modify proteins that wrap around the DNA or even the DNA itself, thus fine tuning this complex process. Interestingly, alterations of these proteins due to mutations leads to aberrant gene regulation and often results in the formation of cancer.
In a paper published in Cell Stem Cell, researchers at the Centre for Genomic Regulation (CRG) led by Thomas Graf in collaboration with scientists from the Institut de Biologie de l’Ecole Normale Supérieure in Paris and from CNAG-CRG and Harvard Medical School, studied this complex process. They focused their attention on an enzyme named Tet2, which plays a crucial role in the formation of pluripotent stem cells and in blood cell differentiation.
Now, Graf and colleagues have described that Tet2 is brought to the DNA by specific proteins with which it can interact. They identified three different transcription factors, each of which can ´take the enzyme by the hand´ and guide it to different sets of target genes needed for cell fate specification. Unexpectedly, therefore a number of different proteins can bring Tet2 to regions of the DNA where and when it is needed.
“We have studied the mechanism by Tet2 acts by monitoring the dynamics of DNA modifications during induced pluripotent stem cell reprogramming. Our data have helped to answer an open question in the field, relevant not only for embryo development and differentiation but also for cell reprogramming and cancer,” explains Thomas Graf, principal investigator of the study and CRG group leader.
Sardina et al. Transcription factors drive Tet2-mediated enhancer demethylation to reprogram cell fate. Cell Stem Cell (2018)