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Non-coding RNAs - What To Be or Not To Be

By Emily Zhou
July 2010

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"Although I will talk about epigenetics in the bottom state, a lot of it has to do with the signal that was triggered by the damaged cells, which could come from the environment," said Rinn. "Pathways in the cell respond to the damage that environmental hazard causes to a human cell." (Photo courtesy of Steve McCaw)

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During his introduction, Tyson said he'd been intrigued by a recent talk by Rinn and wanted to give his colleagues an opportunity to hear of Rinn's work in a field the speaker described as "the mysterious world of Noncodarnia." (Photo courtesy of Steve McCaw)

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"Now we have a global and generic model in which some transcription factor activates polymerase to make lincRNA, then the lincRNA associates with either repressor or activator and translocate to DNA to allow gene repression or gene activation," Rinn told the audience. (Photo courtesy of Steve McCaw)

In a June 3 presentation at NIEHS, guest lecturer John Rinn, Ph.D., explored the role of large non-coding RNAs in establishing the distinct epigenetic states of adult and embryonic cells and their misregulation in cancer. The talk, titled "Large Intergenic Non-coding RNAs (lincRNAs): From Discovery to Mechanism," made a connection between epigenetic alterations and the environmental factors that trigger their ultimate manifestation. NIEHS Program Administrator Fred Tyson, Ph.D. hosted the session.

A professor in the Department of Pathology at the Harvard Medical School and the Beth Israel Deaconess Medical Center and an associate member of the Broad Institute, Rinn (http://www.rinnlab.com/) Exit NIEHS is an expert in the field of lincRNA, which is a previously unrecognized class of mammalian genes that do not encode proteins, but instead function as long RNA molecules.

Rinn's research has advanced the understanding of once disregarded non-coding RNAs and revealed that these lincRNAs play critical roles in both health and disease. As a young research investigator recently awarded the Damon Runyon-Rachleff Innovation Fellowship, Rinn already has many peer-reviewed papers published in top scientific journals such as Nature and Science. He has also received an NIH New Innovator Award.

What to be or not to be

This is the ultimate genomic question, according to Rinn, who opened his seminar by bringing up the fact that "the exact same genome is present in every single cell in our body." However, he asked, how does the cell decide to either stay in its undifferentiated state or become a heart cell, lung cell, or brain cell? "It is the alternate conformation or epigenetic landscape that it [a cell] takes on that will manifest its different cellular physiologies," Rinn explained.

Through the efforts of the NIH Roadmap Epigenomics Program led by NIEHS, it is now known that there are different epigenetic markers, such as the histone code, that control cell identity. But how do these bar codes get put there in the first place and how do they maintain control or epigenetic memory in cell division and repair? Rinn contends that lincRNAs are a merging class of transcripts that are able to rearrange the bar codes to guide cell fates.

LincRNAs and how to find them

Genes that encode lincRNAs are conserved across mammalian evolution. LincRNAs were considered genomic oddities until recently, when Rinn's laboratory identified large numbers of genes encoding LincRNAs. The researchers surveyed genomic regions that have the same chromatin patterns as protein-coding genes, but do not encode proteins. According to Rinn, roughly 7,000 lincRNAs have been discovered in the human genome so far.

Transcript (http://www.niehs.nih.gov/news/newsletter/2010/july/docs/transcript-johnrinn.pdf)  Download Adobe Reader (16KB)

LincRNA functions

Using lincRNA array, Rinn's group has found evidence that lincRNAs are strongly implicated in embryonic stem cell pluripotency regulation and in cell cycle regulation, especially via the p53 pathway. These lincRNAs are independently regulated and are not correlated with its counterpart coding protein.

Rinn and colleagues have discovered that the lincRNA-regulator of apoptosis in reprogramming (lincRNA-ROAR) is a pro-survival signal that plays an important role in the reprogramming process of fibroblast differentiating into embryonic stem cells to prevent apoptosis. The presence of lincRNA-ROAR increases both the number of induced pluripotency cells (iPSCs) and the size of iPSCs.

LincRNA-p21 is a bona fide p53 transcriptional target that acts as a pro-apoptotic signal. LincRNA-p21 is both necessary and sufficient for triggering apoptosis by mechanistically controlling gene-promoter binding to shut off gene transcription. There are more than 30 lincRNAs in the p53 pathways that await further functional studies.

Rinn's talk was part of the popular Keystone Science Lecture Seminar Series, which is organized and sponsored by the NIEHS Division of Extramural Research and Training.

(Yixing [Emily] Zhou, Ph.D., is a postdoctoral research fellow in the NIEHS Laboratory of Signal Transduction.)



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