What Is The Epitranscriptome?

Our genome is made up of 6,000 million pieces of DNA that combine four “flavors”: A, C, G and T (Adenine, Cytosine, Guanine and Thymine). It is our Alphabet.

But to this base we must add some regulation, just like the spelling and grammar of that alphabet: this is what we call Epigenetics.

In epigenetics, there there are “accents,” called DNA methylation, which means having a C or a methyl-C. The first one usually means that a gene is expressed and active, while the second one implies that a gene is silent and inactive.

Our DNA “speaks” when it produces another molecule called RNA (Ribonucleic Acid). Until very recently, it was believed that this molecule was only a poorly regulated intermediate capable of producing proteins (such as insulin, hemoglobin and others) under DNA’s orders.

Epitranscriptome – Epigenetics Of RNA

Now, new research by Manel Esteller, Director of the Epigenetics and Cancer Biology Program of Bellvitge Biomedical Research Institute (IDIBELL), ICREA Researcher and Professor of Genetics at the University of Barcelona, explains that this RNA also has its own spelling and grammar, just like DNA.

These “epigenetics of RNA” are called the epitranscriptome.

“It is well-known that sometimes DNA produces a RNA string but then this RNA does not originate the protein. Because in these cases the alteration is neither in the genome nor the proteome, we thought it should be in the transcriptome, that is, in the RNA molecule. In recent years, we discovered that our RNA is highly regulated and if only two or three modifications at the DNA level can control it, there may be hundreds of small changes in RNA that control its stability, its intracellular localization or its maturation in living beings.”

Dr. Esteller says.

Exciting Research

In human cells, this field did not start to be studied in depth in the last five years.

“For example, we now know that RNA can be methylated just like DNA and in a highly specific way,” says Dr. Manel Esteller, “and even more recently we observed that these epigenetic modifications of RNA may be key in the regulation of “guardian” RNAs, also called non-coding RNAs.”

Epitranscriptome

Credit: IDIBELL

The paper also points out that the epitranscriptome could be altered in some human diseases, while alterations in genes responsible for cancer are also being discovered.

“It will definitely be an exciting research stage for this and the next generation of scientists,”

concludes the researcher.

Different Types Of RNA Modifications

It has been recently discovered that some modification like RNA methylation, may play an active role in regulating some biological process. Also that reversible epitranscriptome modifications might occur on tRNA, rRNA, and mRNAs to regulate gene expression and effect biological process.

Exons of the mRNA

Exons of the mRNA are shown in blue and introns (non-coding sequence) are in red.
a) Alternative splicing involves the removal of introns from the transcript.
b) Adenine is methylated to form m6A modification.
c) m6A forms a uridine rich RNA stem loop near where the m6A modification was made.
HNRNPC protein (involved in pre-mRNA processing) binds to the uridine rich region on the loop leading to the excision of intron.
Credit: Sungyeob, CC BY-SA 4.0

Modifying an RNA molecule requires a significant amount of energy from the cell This high energy cost must mean that the cell deems these modifications to be very important. There are three known types of RNA modifications. rRNA modifications, changes that help with molecular recognition, and mRNA modifications.

rRNA Modifications

rRNA changes take place in areas of high translational activity, such as the PTC(peptidyl transferase center). Some modifications include pseudouridines, 2′-O-methylations on backbone sugars, and methylated bases.

It is not well known what the biological effects of these modifications are on the rRNA molecule but the hypothesis is that they help stabilize the structure and function of the ribosome especially during ribosome replication.

Some functions of these modifications is that the 2′ O methyl does not allow the hydrolysis of the phosphate backbone of the rRNA.

It also allows for more base stacking forces. Which creates a more stable secondary structure. These modifications are required around the PTC to help with translational efficiency.

tRNA Modifications

The known purposes for this kind of epitranscriptome modification is to allow for a bigger difference between the tRNA molecules so that tRNAMet is distinguished from elongator tRNAMet and tRNA stability. Some studies have shown the modifications of tRNA can be a dynamic and adaptive to the changes for the environment.

Examples include the tRNA methyltranserfase (Trm4) which methylates a cysteine group in response to the depletion of nutrients in the body.

mRNA Modifications

Because mRNA is the essential code that changes our biological information from DNA to protein, through transcription and translation, the epitranscriptome modifications that occur on the mRNA must be non-mutagenic and thus most modifications are methylations.

The four sites on mRNA for methylation are N7-methylguanine (at the 5′ cap), N6-methyl adenosine, 5-methylcytosine, and 2′-O-methylation. The cap in mRNA is very important it helps the to recognition by cap-binding proteins to initiate translation, and prevents the degradation of mRNA in the cytosol.

Manel Esteller, Pier Paolo Pandolfi
The Epitranscriptome of Noncoding RNAs in Cancer
Cancer Discovery, 2017; DOI: 10.1158/2159-8290.CD-16-1292

Wang, He, Xiao, Chuan
Dynamic RNA Modifications in Posttranscriptional Regulation
Molecular Cell. 56: 5–12. doi:10.1016/j.molcel.2014.09.001

Top Image: Sungyeob, CC BY-SA 4.0. Schematic of NudC & RppH cleavage of NCIN-capped and ATP-capped RNAs respectively forming 5′-monophosphate RNA product.