Study reveals that cells retain a complete molecular "memory" of their embryonic origins

Researchers at the Dana-Farber Cancer Institute have discovered that adult tissues retain a memory, written on their DNA, of the embryonic cells from which they come. This discovery has led to an even more intriguing phenomenon: memory is fully recoverable: under certain conditions, cells can play the history of their development upside down to activate genes that were active at the time. fetal state.

The results, published online today by the journal Molecular cell, overturn the most common scientific hypothesis that adult tissues carry very few traces of their embryonic origins. The discovery is particularly relevant in the field of regenerative medicine, as it suggests that patient cells can be brought to an earlier stage of development and then matured into adult tissues that can be used to replace diseased or failed organs. . It is also promising for cancer research, particularly on the ability of cancer cells to activate unused genes for a long time to help them spread throughout the body.

"We discovered that adult cells kept a catalog of all genes used early in development – a record of the stage of organ and tissue formation in the embryo," says lead author of the new study, Ramesh Shivdasani, MD. , PhD, Dana-Farber, Brigham and Women's Hospital, Harvard Medical School and Harvard Stem Cell Institute. "Beyond the mere existence of these archives, we were surprised to find that they did not remain permanently locked up but could be accessed by cells under certain conditions." The implications of this discovery for the way we think cell capabilities and the future treatment of degenerative and other diseases, are potentially profound. "

The "embryonic memory" discovered by Shivdasani and his colleagues comes in the form of molecules called methyl groups that bind to DNA in and out of cells. The placement of these methyl groups – to which part of the DNA they bind and in what numbers – determines which genes are active and which are not. The disposition of the methyl groups in a given section of the DNA is known as the methylation scheme.

In this new study, researchers focused on the methylation pattern of regions of DNA called activators. Amplifiers can be considered as keys to enable / disable genes. To activate a gene, the DNA forms a loop that brings an activator closer to the coding part of the gene – the section that contains the plane of manufacture of a protein. Then, with other regions of the DNA and specialized proteins, the genetic code embedded in the DNA is converted to RNA.

During embryonic and fetal development, as cells acquire the specific characteristics of hundreds of adult tissue types, cells "constantly make choices about what kind of cells they will become," explains Shivdasani. "This process, known as cell differentiation, involves cells activating and deactivating different genes with the help of different activators." At each stage of development, particular sets of activators become active, in the same way that individual sections of an orchestra play during different parts of a symphony.

By the time a child is fully formed, the set of active activators remains largely unchanged for the rest of the life (although the liver, for example, grows as the child grows older). his identity as a liver is coherent). For the most part, boosters that were used early in development but are now inactive "seem to have been shut down," says Shivdasani. "They do not seem to have the characteristics of the activity."

One of the distinguishing features of the activators is that some of their sections – where the C molecule of the genetic code is followed by the G molecule – are largely free of methyl groups, a state known as the hypomethylation. This is true even of activators who have been arrested after the end of their role in embryonic development. Scientists, however, did not know how much the cells retain this memory of their oldest incarnations and if it is possible to access these memories.

The results of the new study were enlightening in both respects. In the intestinal cells of adult mice, Shivdasani and his colleagues discovered an almost complete archive of active activators at the developmental stages of intestinal development. In addition, they discovered that in the absence of a protein called Polycomb Repressive Complex 2 (PRC2), most of these activators reactivated resumed their activity after two weeks. (PRC2 is one of the major proteins used by cells to disable specific genes.)

"We have shown that adult cells not only keep a memory of the embryonic and fetal period, but also that under certain circumstances this memory can be found," Shivdasani points out. "The archives are stored safely and can be recalled with remarkable accuracy and precision."

At this stage, researchers can only speculate on why adult cells preserve these molecular memories. One possibility is that they are just vestiges of an earlier phase of the cell lineage – fossils of their evolution. Another is that cells may need to use these memories – to make them live, in reality – to generate new tissue to repair the damage. "If the body needs to regenerate damaged tissue, it may be necessary for the cells in this tissue to replay what has happened in the embryo," says Shivdasani.

The findings could open a new chapter in regenerative medicine, as scientists explore the possibility of exploiting cellular memory to generate replacement tissue for damaged or diseased organs, according to the study's authors. Since this tissue would be derived from the patient's own cells, there would be no risk of rejection by the immune system.

The discovery could also be promising for the treatment of cancer. It is believed that one of the ways in which cancer cells manage to leave the tumor and metastasize is to activate genes that were active during the development of the fetus but then became dormant. Knowing that cells retain a trace of their activators, once active, may suggest new targets for treatments to stop or prevent metastasis in patients.

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The lead author of the study is Unmesh Jadhav, Dana-Farber's PhD, Brigham and Women's and Harvard Medical School. The co-authors are Huafeng Xie, PhD, Dana-Farber and Harvard Medical School; Nicholas K. O'Neill, Zachary Herbert, MS and Shariq Madha of Dana-Farber; Alessia Cavazza, Ph.D., and Kushal K. Banerjee, Dana-Farber, Brigham and Women's and Harvard Medical School; Veronica Saenz-Vash and Huili Zhai, PhD, Novartis Biomedical Research Institutes; and Stuart Orkin, MD, Dana-Farber, Howard Hughes Medical Institute, Harvard Medical School, and Harvard Stem Cell Institute.

The study was funded by the National Institutes of Health (grants R01DK081113, R01DK082889, U01DK103152, F32DK103453, K01DK113067 and P50CA127003); the drug discovery program of the Dana-Farber Cancer Institute-Novartis; a fellowship of the Italian American Cancer Foundation; and gifts from the Lind family.

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