Stem cells are increasingly being used to develop new disease treatments and to understand the basic biology of a number of diseases. However, one of the questions that still needs to be answered regarding stem cells is how they manage to stay in a pluripotent state, instead of differentiating into other cell types. Understanding how pluripotency is maintained has important implications for the optimization of stem cell-based therapies and to the understanding of disease states such as cancer than involve an aberrant undifferentiated state.
Earlier this week in Nature Genetics, Piero Carninci, Alistair Forrest and colleagues (including the FANTOM consortium) reported the identification of a new class of non-coding RNAs that appear to be important for maintaining pluripotency. They name these new RNAs “Non-annotated stem transcripts (NASTs),” since they previously had no known or predicted function. In fact, nearly none of them had even been identified as transcripts before this analysis.
The authors found that NASTs tend to be transcribed from long-terminal repeat (LTR) retrotransposon families, suggesting an important role for this particular “junk DNA”. To figure out what they actually did in the cell, the group knocked down specific NASTs in mouse stem cells carrying a reporter for nanog (a marker of the pluripotent state). Basically, if the NAST in question is important for maintaining pluripotency, knocking it down should reduce the reporter expression (in this case, they’d glow less green under UV light). They tested 77 NASTs, 25 of which affected the expression of the nanog reporter. They confirmed that these NASTs affected pluripotency by also checking the expression of other marker genes.
In a press release, Dr. Carninci had this to say about the study:
“Our work has just begun to unravel the scale of unexpected functions carried out by retrotransposons and their derived transcripts in stem cell biology. We were extremely surprised to learn from our data that what was once considered genetic ‘junk’, namely ancient retroviruses that were thought to just parasite the genome, are in reality symbiotic elements that work closely with other genes to maintain iPS and ES cells in their undifferentiated state. This is quite different from the image given by textbooks that these genomic elements are junk.”
As we delve deeper and deeper into our genome, we continue to find unique functions for “junk DNA”, which we’ve known isn’t actually junk for some time. Studies such as this one, that integrate data from a variety of sources and add functional data to test in silico predictions, will surely yield more exciting discoveries about our genomes.
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