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Cornell Researchers Find Another Epigenetic Code that Affects Messenger-RNA Productivity

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"Research reveals codes that control protein expression." That's the attention-getting headline of an article at the Cornell Chronicle. Researchers from Weill Cornell Medicine led by Dr. Samie Jaffrey found another signaling system that predetermines how much protein a transcribed gene should generate.

The findings may settle a fundamental question in molecular biology -- how the amount of protein generated from a messenger RNA (mRNA) is determined -- and could help scientists develop new therapies for diseases such as cancer where abnormal amounts of protein accumulate.

"This is one of the biggest questions in molecular biology," said senior study author Dr. Samie Jaffrey, the Greenberg-Starr Professor and a professor of pharmacology at Weill Cornell Medicine. [Emphasis added.]

Here's how it works. At the 5' end of a messenger RNA transcript, there's a "cap" region. This cap region was previously thought just to provide a docking structure when the mRNA enters the ribosome, but it turns out that it can also hold information. If the cap has an adenine base (the A in the genetic code), the adenine with its attached sugar ribose (adenosine) can hold up to two methyl groups, which are tags made up of CH3. If the adenosine has one methyl group, it is called m6a. If it has two, it's called m6am. This provides a signaling system for the cell. Think "one if by land, two if by sea."

Jaffrey and team, publishing in Nature, proved experimentally that m6am messenger RNAs are more stable. This means they are more likely to survive longer in the cell and generate more copies of their corresponding protein. Normally, mRNAs are short-lived, degraded by the cell after they produce a protein. That's what happens to the singly methylated m6a forms. If it has the double methyl tag (m6am) it will last much longer and produce more protein. Lindsey explains why stability is related to protein abundance:

They found that mRNAs with m6Am "were highly expressed, meaning that these mRNAs are highly abundant in the cell," Jaffrey said. "They were translated at higher levels and persisted in the cell for a very long time."

Many of these mRNAs contained instructions for making proteins that support cellular metabolism, survival and growth, and these proteins are typically essential for cellular proliferation.

Another player is involved in this coding scheme. It's called FTO ("fat mass and obesity associated protein"). This enzyme can remove methyl groups from the cap adenosines, but it mostly goes after the doubly methylated m6am forms. Because of this, FTO regulates the stability of mRNAs. The Cornell team found that FTO was 100 times more likely to remove a methyl tag from m6am than from m6a.

And then there's another player: DCP2. This enzyme "decaps" mRNAs, facilitating their degradation. Once decapped, mRNAs are degraded by micro-RNAs. The m6am RNAs, however, are more resistant to decapping by DCP2. This new epigenetic code helps explain why some mRNAs are more robust against degradation than others.

Why is this important? Without this signaling system, bad things can happen!

Since m6Am promotes cell growth and proliferation, abnormalities in FTO and m6Am levels can potentially contribute to cancer by encouraging uncontrolled cell division and by making it difficult for malignant cells to die.

"We've known for years that FTO is a critical regulator of cell function," Mauer said. "Misregulated FTO is associated with severe developmental defects and diseases such as cancer."

In their own words, the researchers consider this a coding system. "An internal code in cellular molecules called messenger RNA predetermines how much protein they will produce," Lindsey says. In the paper, the authors explicitly use the words code and information. In the Introduction, they say this:

An emerging concept in gene expression regulation is that a diverse set of modified nucleotides is found internally within mRNA, and these modifications constitute an epitranscriptomic code.

And they repeat the concept in the concluding Discussion:

Here we identify m6Am as a dynamic and reversible epitranscriptomic mark. In contrast to the concept that epitranscriptomic modifications are found internally in mRNA, we find that the 5′ cap harbours epitranscriptomic information that determines the fate of mRNA. The presence of m6Am in the extended cap confers increased mRNA stability, while Am is associated with baseline stability. m6Am has long been known to be a pervasive modification in a large fraction of mRNA caps in the transcriptome, making it the second most prevalent modified nucleotide in cellular mRNA. Dynamic control of m6Am can therefore influence a large portion of the transcriptome.

Interestingly, the code is also location-dependent:

The concept of reversible base modifications is appealing since it raises the possibility that the fate of an mRNA can be determined by switching a modification on and off. Our data show that FTO is an m6Am 'eraser' and forms Am in cells. FTO resides in the nucleus, where it probably demethylates nuclear RNA and newly synthesized mRNAs. Demethylation of cytoplasmic m6Am mRNAs may be induced by stimuli that induce cytosolic translocation of FTO.....

.... Thus, the location of the modified nucleotide and the specific combination of methyl groups on adenosine residues encode distinct functional consequences on the mRNA.

The essence of a "code" is that it bears information. This code resembles an "if-then" algorithm in software. Speaking mechanistically, there's nothing about a methyl group that should indicate, "keep this attached molecule stable against degradation." Instead, the coding system works because all the players recognize the convention.

The methyltransferase enzyme has to "know" which mRNA needs a second methyl group to confer stability, because it has an essential role. The FTO enzyme "knows" to concentrate on demethylating one tag from the m6am forms, and to stay inside the nucleus unless stimulated to go after m6am RNAs in the cytoplasm. And DCP2 has to know to avoid uncapping the doubly-methylated m6am transcripts. Because the players know the signal, the cell produces the appropriate quantity of proteins corresponding to their importance.

What we see here is another Signature in the Cell. Intelligent design advocates are not surprised to find codes and switches in irreducibly complex systems. In fact, we expect that this finding will stimulate the discovery of additional codes, such as those that decide which mRNA transcripts should be treated as more important than others.

Darwinian evolution, by contrast, has a big challenge in explaining how multiple players mutated together by chance to hit upon a language convention. What do unguided, blind processes know about codes? What do they understand about information? In short, nothing.

Photo: Samie Jaffrey, via Cornell University.