In Search of RNA Epigenetics: A Grand Challenge

from Zone in with Zon by Jerry Zon

  • Methylated riboA and riboC are the most commonly detected nucleobases in epigenetics research
  • Powerful new analytical methods are key tools for progress
  • Promising PacBio sequencing and novel “Pan Probes” reported   

In a Grand Challenge Commentary published in Nature Chemical Biology in 2010, Prof. Chuan He at the University of Chicago opined that “[p]ost-transcriptional RNA modifications can be dynamic and might have functions beyond fine-tuning the structure and function of RNA. Understanding these RNA modification pathways and their functions may allow researchers to identify new layers of gene regulation at the RNA level.”

Like other scientists who get hooked by certain Grand Challenges, I became fascinated by this possibility of yet “new layers” of genetic regulation involving RNA, either as conventional messenger RNA (mRNA) or more recently recognized long noncoding RNA (lncRNA). Part of my intellectual stimulation was related to the fact that some of my past postings have dealt with both lncRNA as well as recent advances in DNA epigenetics, so the notion of RNA epigenetics seemed to tie these together.

After doing my homework on recent publications related to possible RNA epigenetics, it became apparent that this posting could be logically divided into commentary on the following three major questions: what are prevalent epigenetic RNA modifications, what might these do, and where is the field going? Future directions were addressed by interviews with two leading investigators: Prof. Chuan He, who is mentioned above, and Prof. Tao, who has been involved in cutting edge methods development.

RNA Epigenetic Modifications

More than 100 types of RNA modifications are found throughout virtually all forms of life. These are most prevalent in ribosomal RNA (rRNA) and transfer RNA (tRNA), and are associated with fine tuning the structure and function of rRNA and tRNA. Comments here will instead focus on mRNA and lncRNA in mammals, wherein the most abundant—and far less understood—modifications are N6-methyladenosine (m6A) and 5-methylcytidine (m5C).

structures

Three Approaches to Sequencing m6A-Modified RNA

Discovered in cancer cells in the 1970s, m6A is the most abundant modification in eukaryotic mRNA and lncRNA. It is found at 3-5 sites on average in mammalian mRNA, and up to 15 sites in some viral RNA. In addition to this relatively low density, specific loci in a given mRNA were a mixture of unmodified- and methylated-A residues, thus making it very difficult to detect, locate, and quantify m6A patterns. Fortunately, that has changed dramatically with the advent of various high-throughput “deep sequencing” technologies, as well as other advances.

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