The twitch of a butterfly’s wing can initiate a cascade of increasingly substantial events, culminating in changes that are both profound and far-reaching. That’s the gist of any butterfly effect, whether it’s the formation of hurricane, the climax of a Hollywood movie, or the differentiation of a stem cell. A stem cell’s fate, it turns out, can hinge on a single protein, one that stays in telomeres but accounts for genome-wide changes.

The protein, telomer repeat binding factor 1 (TRF1), may “twitch” one way or another. If TRF1 is upregulated, a cell may enter or maintain the pluripotent state. If TRF1 is abrogated, a cell may activate its cell-fate programs and hasten toward its differentiated state.

Between the twitch and a cell’s differentiation state is a chain of intermediate events that has been uncovered by scientists based at the Spanish National Cancer Centre (CNIO). These scientists, led by María A. Blasco, PhD, found that TRF1 regulates TElomeric Repeat-containing RNAs (TERRAs), which are long noncoding RNAs transcribed from telomeres. TERRAs act on key genes for pluripotency through the polycomb proteins, which control the programs that determine the fate of cells in the early embryo.

According to Blasco and colleagues, TERRAs account for genome-wide binding of polycomb and the accumulation of polycomb H3K27me3 repressive marks at pluripotency genes. In a paper (“TERRA regulate the transcriptional landscape of pluripotent cells through TRF1-dependent recruitment of PRC2”) that appeared August 20 in eLife, the scientists report that these epigenetic changes help maintain mouse embryonic stem cells in a naïve state.

“We find that TERRAs are enriched at polycomb and stem cell genes in pluripotent cells and that TRF1 abrogation results in increased TERRA levels and in higher TERRA binding to those genes, coincidental with the induction of cell-fate programs and the loss of the naïve state,” the article’s authors wrote. “These results are consistent with a model in which TRF1-dependent changes in TERRA levels modulate polycomb recruitment to pluripotency and differentiation genes.”

It has been known for about 15 years how to return the power of pluripotency to cells by acting on certain genes. However, the researchers noticed that this recipe did not work if the TRF1 gene was turned off. Moreover, TRF1 was one of the most activated genes when pluripotency was induced. These facts intrigued the researchers. Why was TRF1, a gene whose product is only found in telomeres, activated so much, and how could this be essential for pluripotency?

“We could not understand how a gene that deals with telomere maintenance has such a profound effect on a global process like pluripotency,” said Blasco, the study’s senior author and head of CNIO’s Telomeres and Telomerase Group.

To find an explanation, Blasco and colleagues decided to carry out a random search by analyzing the changes in the expression of the entire genome when the expression of TRF1 was prevented—something like blindly casting a large net into the sea to see what is in it. “We saw that TRF1 had an enormous, but very organized, effect,” explained Blasco.

The expression of many genes was altered, and more than 80% of them were directly related to the phenomenon of pluripotency. The researchers also noted that many of these genes were regulated by polycomb, a protein complex that is very important in the early stages of embryonic development and that directs cells to specialize into the different cell types of the adult body.

But they still did not understand what the link between polycomb and TRF1 was. Last year, however, Blasco’s group discovered that the TERRA molecules that are produced in telomeres communicate with polycomb and that together they are involved in building the telomere structure.

The researchers decided to analyze the interaction between TERRA and the entire genome, and sure enough, they found that TERRA stuck to the same genes that were regulated by polycomb. This suggested that TERRA was the link between TRF1 and pluripotency.

In normal induced pluripotent stem cells, TRF1 is highly expressed, the Polycomb (PRC2) complex (encompassing EDD, EZH2, and Suz12) is weakly bound to the genome, and pluripotency genes are expressed. After TRF1 depletion, the expression of TElomeric Repeat-containing RNAs (TERRAs) is increased, resulting in PRC2 recruitment to genes involved in the control of pluripotency and differentiation. Increased binding of PRC2 to its target genes is concomitant with an increase in the abundance of the H3K27me3 polycomb repressive mark at some of these sites, inducing cell-fate programs. [CNIO].
TRF1 “exerts a butterfly effect on the transcription of pluripotent cells, by altering the epigenetic landscape of these cells through a novel mechanism, which involves TERRA-mediated changes in the action of polycomb,” the researchers indicated in eLife.

As Rosa Marión, PhD, first author of the study, explained, “These findings tell us that TRF1 is essential for reprogramming specialized cells and for maintaining pluripotency.” By peering into the black box that is pluripotency, the Blasco group may contribute to the advance regenerative medicine applications, such as the use of organ culture for transplants.

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