Epitranscriptomics - Complex code points to Design

Epigenetic markers on RNA are necessary for life


Excerpts: "There was a similar reaction to epigenetics more than a decade ago, when it became clear that chemical modifications regulating genes are frequently out of whack in cancer. Companies rushed to develop drugs against proteins responsible for making, removing, and recognizing chemical modifications on genes—often referred to as the writer, eraser, and reader proteins. With the discovery of parallel writer, eraser, and reader proteins working on RNA, epitranscriptomics is looking like a promising, untapped area for drug discovery.

...But there’s another parallel to epigenetics that’s less optimistic: thus far, epigenetic drugs have been a disappointment. “Epigenetics turned out to be a lot more complicated than the community originally thought,” says Chuan He, a professor of chemistry at the University of Chicago.

Scientists knew that METTL3 placed a methyl on a specific nitrogen in adenosine, one of the four building blocks of RNA. This modified building block is called N6-methyladenosine, or m6A for short. Beyond m6A, chemists had cataloged some 150 different chemical modifications to RNA in bacteria, plants, and animals. If He could find an enzyme that removed the methyl groups, it would suggest that there was an undiscovered RNA control system in cells, analogous to epigenetic controls in DNA.
That technique allowed the creation of the first map of m6A. The results were stunning. “We thought that m6A was going to be all over the place, kind of random,” Jaffrey says. Instead, the researchers saw that methyl marks tended to cluster near an area called the stop codon, and only on certain mRNA transcripts. “It was so specific, it just knocked our socks off.

An even closer inspection revealed that many of the mRNAs containing m6A were linked to differentiation and development, the same functions that were affected in Fray’s stunted plant embryos. “We were amazed,” Jaffrey says.
Work by Stanford University geneticist Howard Chang helped change that attitude. Chang showed that without METTL3, mouse and human embryonic stem cells grow uncontrollably and never undergo their normal maturation process, called differentiation, in which they change into specialized cells, such as muscles, neurons, or white blood cells (Cell Stem Cell 2014, DOI: 10.1016/j.stem.2014.09.019). A few months later, Rechavi’s group published a similar study, with an added step showing that mouse embryos missing METTL3 died before birth.

It was becoming clear that m6A was not just some random mark on a transcript. Even though the methyl group is physically small, it has a big effect on RNA. The modifications can coax RNA to assume a different 3-D structure. He’s lab also began studying newly discovered proteins dubbed readers, which have small pockets that bind m6A. He showed that one reader specifically binds m6A to flag an mRNA for destruction. Another reader binds m6A to help spur protein production. He’s elucidation of these reader proteins increased interest in epitranscriptomics for scientists and investors, says Larry Lasky, a partner at the Column Group, a venture capital firm. “It started to look and smell like epigenetics.

In addition to the m6A erasers, a growing body of work is uncovering the importance of the m6A readers. Earlier this month, He’s lab showed that an m6A reader protein called YTHDF1 is an important control switch in the immune system and that inhibiting it might dramatically boost the efficacy of existing checkpoint inhibitors, a popular class of cancer immunotherapy (Nature 2019, DOI: 10.1038/s41586-019-0916-x). “I think a lot of immunotherapy companies will jump into epitranscriptomics once they read the paper,” He says.

And this isn’t the first known link between epitranscriptomics and immunotherapy, Accent’s Copeland says. His firm has been studying an enzyme called ADAR1—which stands for adenosine deaminase acting on RNA—that modifies adenosine bases in RNA. Studies from academic labs show that some tumors depend on ADAR1 in ways that normal cells do not. One study suggests that blocking ADAR1 could make certain drug-resistant cancers vulnerable to checkpoint inhibitors (Nature 2018, DOI: 10.1038/s41586-018-0768-9).
Other labs entering the fray are uncovering new proteins that read, write, and erase RNA modifications, with links to additional types of cancer and other diseases. The scope of epitranscriptomics could be enormous. “That’s what excites us about the field,” says Blundy, Storm’s CEO. “There are many, many RNA pathways that are regulated through modifications.” ”

My comment: There are only a few different types of epigenetic markers on DNA but the number of different epigenetic markers on RNA is about 150. DNA is needed for producing functional programmable RNA molecules. Readers, writers and erasers point to a designed cellular system, where changes don't occur just randomly but by accurate mechanisms induced by nutrition, stressors, sensory stimuli, climate, pheromones etc. Erasers make this system dynamic and reversible.

You may have heard about a theory claiming that changes in organisms occur by random chance and selection. These newest findings on RNA epigenetics refute those hollow claims.