Head of epigenetics, associate director of research, Babraham Institute
• Head of developmental genetics and imprinting, Babraham Institute — 1992-2011
• Fellow, Lister Institute of Preventative Medicine at Institute of Animal Physiology — 1987-1993
• Postdoc, AFRC Animal Research Station, University of Cambridge — 1985-1987
Researchers from the Babraham Institute this week reported in Nature Cell Biology on the discovery that a highly conserved and abundant long non-coding RNA, called H19, acts as a reservoir for microRNA-675, which in mice slows down the growth of placentas before birth.
In their experiments, the investigators found that placentas lacking H19 continue to grow, and that over-expression of miR-675 in different embryonic and extra-embryonic cell lines reduces their proliferation.
“Targets of the miRNA are up-regulated in the H19 null placenta, including the growth-promoting insulin-like growth factor 1 receptor gene,” the team wrote in their paper. “Moreover, the excision of miR-675 from H19 is dynamically regulated by the stress-response RNA-binding protein HuR.”
This week, Gene Silencing News spoke with Wolf Reik, the study's senior author, about the findings.
Perhaps we could start with a little background on your lab.
We've been in epigenetics research for as long as it's been called epigenetics, really — more than 20 years. In the early days, [we started with research into] genomic imprinting, and now on more general epigenetic mechanisms, particularly epigenetic reprogramming.
This work stems from previous work you had done on H19. Can you talk about your understanding of it going into these studies?
H19 is probably one of the first, if not the first, discovered non-coding RNAs in the genome. It was discovered more than 20 years ago, and at that time people didn't really know about non-coding RNA — it was a complete enigma because basically there were only protein-encoding RNAs in the genome. It was really strange for a long time, how this large RNA could be there, very highly expressed … in every cell. The mystery was enhanced when this RNA was discovered to be imprinted, meaning that it was only expressed from the maternal chromosome, not the paternal one.
It was variously implicated in tumor suppression, and that was intriguing … and we then discovered about three or four years ago that it was one of the most conserved non-coding RNAs in the whole of the mammalian kingdom. This enhanced the mystery even more. It was kind of standing up all the time saying, “I'm really important. Please find out what I'm doing.”
It then became apparent through a paper published about four years ago that not only was [H19] a non-coding RNA, but it also harbored a microRNA. This is, again, unusual because most microRNAs are not part of other RNAs; they're transcribed by themselves. But here was a long non-coding RNA doing something really important and harboring a microRNA.
This provided a rational kind of approach to the problem of trying to understand what the long RNA was doing harboring the microRNA, and the microRNA was potentially the business end of the long RNA.
Can you give a snapshot of what you found out about H19 and the microRNA?
Basically, we found out that while the microRNA is produced by the H19 RNA, mostly the processing of the microRNA is suppressed. This, again, is unusual for a microRNA because if it is made, it is usually processed without any delay and the processing usually destroys the host transcript — in this case, H19.
But that wasn't the case. In most tissues, you only see H19; you don't see the microRNA because there is a very potent mechanism that suppresses [its] production. It is only in the placenta that we saw accumulation of the microRNA. In the second half of gestation when the placenta slowly stops growing, the microRNA appeared, and there was a kind of regulated release of the microRNA specifically happening in the placenta.
We then figured out that this controlled release of the microRNA slows the growth of the placenta. This is really important because, before giving birth, you actually need to stop growth of the placenta in preparation for normal birth. That, we think, is the main function of the microRNA.
Are there plans for taking these findings further?
All of this is based on mouse experiments. What is really important is to ask if the same is true of the human placenta. It could be a really interesting candidate in problems with placental growth as they occur in pre-eclampsia, for example, which is a condition where the placenta grows aberrantly and mothers have hypertension and problems giving birth. It's also potentially interesting to see if the microRNA could be implicated in intra-uterine growth restriction, a [condition] where you often have small placentas and small babies.
I think if it is found that this molecule is as important in the human placenta as it is in the mouse placenta, then it could provide us with new diagnostic markers for these adverse conditions, and potentially with ideas for therapy of those conditions.