Stopping the Stem Cell State

Scientists can now create cells that closely resemble embryonic stem cells in the lab. But what happens next? Because the use of these cells, called induced pluripotent stem (iPS) cells, to treat disease will ultimately depend on how we learn to direct their fate, we also need to figure out how they stop being stem cells – a process that naturally takes place right at the beginning of embryonic development. “The system must be shut off before differentiation into the various cell types can proceed,” says Dr. Jacob Hanna of the Weizmann Institute’s Molecular Genetics Department. “We have gotten somewhat proficient at getting the cells to revert, but very little is known about the termination of the iPS program.”

To investigate, Hanna and research student Shay Geula teamed up with Prof. Gideon Rechavi of Chaim Sheba Medical Center in Tel Aviv, and their findings recently appeared in Science. Hanna’s group is making strides in the field of iPS cell research; Rechavi’s group is one of the world’s leading experts in another little-known area, called RNA methylation.

Methylation is a basic biochemical process: A chemical “methyl” group gets attached to a genetic sequence, blocking it off from further use. In the better-known version, DNA methylation, the process is often described as a lock – hard to open again and relatively long-lasting. Some types of methylation can even be passed down to the next generation. So when Rechavi’s group and others noted that the short-lived genetic sequences of RNA can also be marked by methyl groups, it was unclear to what purpose.

The researchers identified an enzyme – Mettl3 – that attaches methyl groups to the RNA of mammalian cells. To see whether this action plays a role in undoing the stem-cell state, they silenced the gene for this enzyme in mouse embryos. The consequences were devastating: The embryos were not viable for more than a few days. Development didn’t progress as cell differentiation could not proceed properly.

A closer look at the actions of Mettl3 revealed that it attaches its methyl groups to the exact sequences that code for pluripotency – the capacity to become any cell type. Rather than simply locking these sequences, the methylation causes them to be broken down.

Hanna: “These findings showed that, on the one hand, RNA methylation plays a crucial role in embryonic development and, on the other, that it is not enough to reinstate the stem cell program. It must be turned off again, at the right time and in the right way, for the next step in cell differentiation to take place. RNA methylation is the dominant mechanism that safeguards adequate dismantling and decay of the stem cell state.”