RNA Modifications Mapped, Major Epigenetic Breakthrough

RNA Modifications, RNA Modification

With the mapping of RNA modifications of the base A, the science of epigenetics continues to unfold as one of the most important discoveries in modern times. 

DNA and RNA have been described as linear chains of four bases: nucleotides A, G, C, and T for DNA; and A, G, C, and U for RNA. [1] Those four bases can develop into much larger variety due to chemical modifications that decorate nucleic acids. [2] Overall, we know that there are about a dozen known variants in DNA, but RNA is even more surprising with more than 140 alternative forms. 

While DNA is mainly about storing genetic information, RNA molecules are involved in many different regulatory activities in addition to translating genes into proteins. [3] So, it is not that surprising that RNA has more alternative forms. The multitasking power of RNA means that they are the first molecules of life and likely to promote evolution of modified nucleotides. [4] 

DNA Methylation and Histone Modification

In recent decades, epigenetic researchers have mostly explored two mechanism’ that regulate our genetic expression: DNA Methylation and the other is Histone Modification. During this time, the study of histones has been mostly the primary focus of epigenetic modification research.  [5]

Major Discovery, RNA Modifications of the Base A Mapped

However, on January 1st, 2016, the science of epigenetics took another exhilarating step forward to better describing our genetic expressions. A study by Dan Dominissini, Chuan He, and Gidi Rechavi published in The Scientist Magazine showed for the first time that nucleotides in RNA may be modified by methylation; these modified nucleotides also affect genes’ behaviours. [6]

Among the 140 variants of RNA modifications of the nucleotides studied, methylation of base A at the N6 position (m6A) appears to be most prevalent epigenetic mark in eukaryotic mRNA. [7] 

Technological Advancements Enabled Transcriptome-Wide Mapping of m6A

The identification of m6A in RNA has been known for about 40 years old, but the lack of quantification methods and efficient molecular mapping made it difficult to completely understand the implication of the modification. [8]

A breakthrough came in 2012 when the combined power of traditional antibody-mediated capture techniques and NGS (next generation sequencing) was utilized to perform high resolution transcriptome-wide mapping of m6A. [9] The combination of both methods is now known as m6A-seq. Analysis by using m6A-seq successfully identified more than 12,000 sites of mRNA methylated molecules derived from about 7,000 protein-coding genes. [10] Most of the expressed genes were shown to be methylated, indicating that there was a widespread modification of m6A. [11] The study also found that m6A decorates about 250 sequences of lncRNAs (long non-coding RNAs) including the well-characterized ones. [12]

It is now understood that m6A plays important role in expression of diverse transcripts, but the study to understand how m6A marks are regulated and how they affect various cellular processes are still in the initial phase. [13]

RNA Epigenetics in Motion

To get better understanding of how the new epigenetic mark affects pathological and physiological processes, researchers need to study the molecular mechanisms by which RNA stability, alternative splicing, and translation efficiency are controlled by m6A regulation. [14] It is clear that various cellular and physiological functions are associated with m6A, but the best illustration to describe its important roles to control processes at cellular level is its involvement in early embryogenesis.

Alterations in global gene expression, orchestrated by epigenetic regulation coordinate cell-fate decisions. [15] Two well-known epigenetic marks including histone modifications and DNA methylation mediate ESC (embryonic stem cell), and it turns out that m6A modification possesses the same abilities. [16] Researchers will gain better understanding of how diverse cellular processes are regulated as the list of known RNA epigenetic marks continues to expand. When it happens, we will be able to accurately reveal RNA marks analogous to histone and DNA epigenetic marks; various modifications of protein, RNA, and DNA will also enrich the knowledge of diversity, adaptation, and development of complex organisms.

The World of Epigenetics Continues to Amaze

With the mapping of RNA modifications of the base A, the world of epigenetics has just got bigger. [17] As technology allows researchers to study, gather data, and make more complete accurate conclusions, science of epigenetics will revolutionize civilization and bring extensive understanding on how genes are expressed.

An eventual next step will be to conduct research to better understand what environmental factors trigger methylation patterns and how the unfavorable modifications can be reversed.



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    By: Dr. Suhasini Bhatnagar

    Dr. Suhasini Bhatnagar has done her PhD in Medical Genetics and sub specialization of human population genetics from the Sanjay Gandhi Postgraduate Institute of Medical sciences in 2001.For this she had her GATE percentile 96.8 and was UGC-NET qualified.She has more than 15 international publications and has attended one International Conference and several National Conferences.She did her post graduation in Biotechnology from The M.S.University of Baroda in 1992 for this she got the deptt. of Biotechnology fellowship.She was awarded Fellowship by DBT for pursuing M.Sc in biotechnology.She was granted CSIR-JRF NET fellowship Council of Scientific and Industrial research.She had done her graduation from Botany (Hons.) in 1990 from Gargi College.She was awarded The Prativa Mukherjee Award for securing highest marks in Botany in 1987.She has a teaching experience of more than 8 years and research experience of 9 years.

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