Researchers unravel the mystery of the role of a silent key protein in a gene

A long-running debate about how silent gene proteins mark their targets has been resolved by researchers at Massachusetts General Hospital (MGH). Their conclusions, reported in Structural and Molecular Nature Biology, also explained some mysteries about the behavior of this protein, known as Polycomb repressive complex 2 (PRC2).

PRC2 helps regulate whether genes are active (“on) or silent (” off “). The role of PRC2 in gene mutation is crucial throughout life, from embryo formation to old age. determining whether genes that inhibit malignant growth have turned tumors on or off, which has led pharmaceutical companies to focus on developing anti-cancer drugs.

But the mystery about PRC2 remained unsolved for years: How was the protein able to target specific genes? Significant progress took place in 2008, when a team led by Jeannie Lee, MD, PhD, a researcher in the Department of Molecular Biology at MGH, recommended that RNA work as an employer for PRC2. RNA (or ribonucleic acid) is a DNA-like molecule found in cells. RNA is usually a messenger that makes DNA claims by spelling out the code to make proteins, but that is not true here. Instead, Lee and her colleagues showed that RNA acts as a “free agent” that binds to PRC2. RNA then targets PRC2 to a specific gene to keep it quiet.

After Lee and her colleagues reported their findings, dozens of other papers were subsequently published that supported the theory that RNAs employ PRC2 as an essential step in gene disruption. However, studies from several prominent labs have challenged these conclusions, leading to ongoing and often heated debate about the relationship between PRC2 and RNA. Critics questioned Lee’s findings for two reasons:

• PRC2 is not specific and can bind to any RNA (some scientists have noted that the protein is “promiscuous”), suggesting that RNA may not be a feature in targeting PRC2 for gene harassment.
• The interaction between PRC2 and RNA often occurs at active genes, an indication that this relationship is not important for the silencing of specific genes.

The new study resonates with both critics. In the first case, Lee explains, think of PRC2 as a letter that must be delivered by a postal carrier, but does not have an address. How does the postal carrier know where to deliver it – that is, what is the “address” of the gene that is targeted for silence? “The address is written on the RNA,” Lee said. “RNA is a true copy of DNA, where our genes are encoded.” Lee and her colleagues identified “motifs,” or specific sequences in RNA, that allow PRC2 to be identified. The RNA “address” then directs PRC2 to a specific gene location. This ability has been previously suggested, but Lee and her team are now shedding new light on how motifs produce specific interactions between PRC2 and RNA that enable targeting.

Lee uses another analogy to explain why PRC2 and RNA often interact at genes that are not silent. In the past, light bulbs could not be turned on or off, but the dimmer switch device allowed them to cast soft or bright light. Similarly, genes are not always fully turned on or off, and PRC2 acts as a dimmer switch.

We say that the genes are ‘forward,’ but emit a little light. If you removed the Polycomb-RNA interaction, the genes would turn up and shine brightly. “

Lee, Lead Author, Professor, Genetics, Harvard Medical School

Resolving past conflicts about how PCR2 interacts with RNA, Lee says, this new integrated model advances basic science and provides valuable insights for medical developers- new treatments.