Cellular Senior Moments

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(l-r) Dr. Zohar Mukamel, Zohar Shipony and Prof. Amos Tanay
Aged cells, just like aged humans, have memory issues, according to a new study at the Weizmann Institute of Science. Insights gained by the study of a particular form of cellular memory may shed new light on the development of cancer and on the use of stem cells in therapy.

Our cells have a great deal to remember. Their genetic memory has long been known to be remarkably accurate: The rate of mistakes, or mutations, in the DNA during cell division is as low as one in millions or even billions of genetic letters, so that all the cells in our body – which have originated from a single cell, the fertilized egg – have the same genes. But as reported recently in Nature, Weizmann Institute scientists have now found that the cells’ epigenetic memory, the one not encoded in their DNA, is fraught with a surprisingly high rate of mistakes.

The scientists have focused on a particular epigenetic mechanism in which a chemical tag, a methyl group, is attached to the DNA. The activity of the cell’s genes is in part dictated by the distribution of these tags, the DNA methylation pattern. The methyl tags help regulate the turning of genes on and off, which, among other things, determines the cell’s identity – whether it will become part of the skin, the kidneys, the brain or some other tissue.

Selection of cells by CellCelector, a technology used in the research on cellular epigenetic memory: The machine identifies a single cell (circled in red) in a cell culture and removes it for study
Using innovative techniques they developed for mapping memory patterns, which combine massive DNA sequencing with mathematical algorithms, the scientists found that when the methylation pattern is passed on to daughter cells in the same organism during cell division, mistakes occur in as often as one in 200 - 1000 tags. The mistakes accumulate with each division, so that the methylation of an old cell – one that has been produced by a large number of divisions – can be completely garbled. In this sense, the passing on of epigenetic memory resembles the game of Chinese whispers, or broken telephone.
This revelation suggests that mistakes in epigenetic memory may make older cells more liable to undergo malignant transformation. Just as the build-up of minerals prevents older people from making full use of their joints, so the accumulation of epigenetic mistakes can prevent an older cell from responding properly to various signals, among them the signal to self-destruct when the cell is about to lose its normal growth control and turn cancerous.
A colony of human skin cells (circled in red) is picked out by the CellCelector
The “Chinese whispers” discovery may prove useful in fighting cancer. By studying the pattern of epigenetic mistakes in tumor cells, it might be possible to chart their “family trees,” that is, to trace their origins to a particular site in the body. This, in turn, can affect treatment decisions. In addition, epigenetic mistakes may serve as markers helping to distinguish cancerous cells – which undergo so many divisions they accumulate these mistakes in huge numbers – from cells that are old but healthy.

Moreover, the study suggests that even in the same tissue, individual cells – for example, certain cells of the spleen or liver – differ from one another in their methylation patterns. Such findings need to be taken into consideration in the development of diagnostic assays or drugs, because this variability may affect the effectiveness of a medication.

The Weizmann researchers have also found that in contrast to mature cells, embryonic stem cells have an excellent epigenetic memory. For instance, when stem cells are maintained in their immature cell state for a while, they preserve a stable methylation pattern despite numerous divisions. How do these cells remember so well who they are?

The surprising answer is that they do not listen to their ancestors: The researchers have shown that unlike what happens in mature cells, epigenetic memory in embryonic stem cells is not maintained through the transmission of stored information to the newly divided cells. Rather, the pattern of methyl tags is erased and created anew continuously during and between cell divisions. Thanks to this dynamic mechanism, an accumulation of epigenetic mistakes is avoided.

This discovery explains what happens when mature cells are genetically reprogrammed into stem cells. Scientists who discovered the possibility of such cellular reprogramming – which promises to ensure an unlimited supply of stem cells for therapy – were awarded the 2012 Nobel Prize in medicine; but until now it was unclear how a mature cell could be suddenly induced to “remember” the methylation pattern it had as a stem cell. The Weizmann study has resolved the mystery: When a mature cell is reprogrammed, machinery capable of erasing and rewriting methyl tags is turned on, so that the epigenetic memory state of an embryonic stem cell is rapidly reconstituted.

The study was performed by Prof. Amos Tanay of the Computer Science and Applied Mathematics, and Biological Regulation Departments and his research team, including lead authors Zohar Shipony and Dr. Zohar Mukamel; together with Netta Mendelson Cohen, Gilad Landan and Elad Chomsky; Weizmann researcher Dr. Nir Friedman and Dr. Shlomit Reich-Zeliger from his group in the Immunology Department; and Drs. Yael Chagit Fried and Elena Ainbinder of the Department of Biological Services.
Prof. Amos Tanay’s research is supported by the Helen and Martin Kimmel Award for Innovative Investigation; Pascal and Ilana Mantoux, Israel/France; the Wolfson Family Charitable Trust; the Rachel and Shaul Peles Fund for Hormone Research; Moise and Carol-Ann Emquies, Santa Monica, CA; and the estate of Evelyn Wellner.
Dr. Nir Friedman’s research is supported by the Nella and Leon Benoziyo Center for Neurological Diseases; the Clore Center for Biological Physics; the  Henry Chanoch Krenter Institute for Biomedical Imaging and Genomics; the Victor Pastor Fund for Cellular Disease Research; the Abraham and Sonia Rochlin Foundation; the Adelis Foundation; the Norman E. Alexander Family Foundation; the Jeanne and Joseph Nissim Foundation for Life Sciences Research; the Crown Endowment Fund for Immunological Research; the estate of John Hunter; and the estate of Suzy Knoll. Dr. Friedman is the incumbent of the Pauline Recanati Career Development Chair.