New Australian study finds noncoding DNA has epigenetic regulation like coding RNA

Only a small part of the DNA in eukaryotes (organisms with a cell nucleus) codes for the production of the proteins. The rest is called non-coding, or previously, “junk” DNA. In humans, the amount of non-coding DNA has been estimated to account for 98% of the total DNA strands.

Some of these non-coding parts of the DNA are copied into small and large RNAs by a process known as transcription. Transcripts not translated into protein that are more than 200 nucleotides in length are called long non-coding RNAs (lncRNA). These lncRNAs come from different places in the genome. They may come from in between exons and introns of a gene or from in between the genes themselves. 

Over the past 20 years, much research has focused on finding out if there is some function for the non-coding portions of the DNA. It has already been established that protein coding exons have a particular nucleosome arrangement allowing for cellar accessibility. An article appearing Sept. 27 in the journal Epigenetics & Chromatin reports a similar arrangement of nucleosomes in non-coding RNA. This suggests that it is important for the cell to access these non-coding regions just as it is important for the cell to access coding regions.

The study was carried out by Pinki Dey and John Mattick, both from the School of Biotechnology and Biomolecular Sciences, of the University of New South Wales in Sydney, Australia. 

The researchers examined published libraries of genomic data obtained by a technique known as nucleosome mapping. A nucleosome is a DNA structural unit where DNA is wound around eight proteins, known as histones, that act like spools. It provides the means for packing long strands of DNA into a small space. 

The nucleosomes for these studies were obtained primarily from activated human CD4+ T cells. This is a type of immune cell found in the blood that helps other immune cells to defeat an invader. 

Nucelosome positions

One of the researchers' major findings is that the nucleosome position pattern for exons in IncRNA is the same as the pattern in protein coding exons.

Intron retention

Another interesting finding relates to a phenomenon known as intron retention. For protein coding regions, sections of the DNA strand are classified either as exons (those that cod for a protein) or introns (those that do not code for a protein). Most of the introns are spliced out as the RNA matures into a messenger RNA that will be translated by the ribosome for protein production, but a few introns are retained. 

Traditionally, the retained introns were regarded as “noise” and overlooked. More recent studies have shown that the retained introns play a role in normal gene expression, and also in cancer. 

IncRNA also have introns and exons

The researchers found that retained introns occur in over 50% of the long non-coding RNAs (lncRNAs) they examined. The retained introns are mostly quite short, about 5% of the average length of all human introns. 

This widespread intron retention (IR), the authors note “raises intriguing questions about the relationship of IR to lncRNA function and chromatin organization.”

Histone modifications

Part of what controls intron retention are certain epigenetic marks on histone proteins, which are part of the nucleosome unit. These marks do not affect the DNA informational sequences but may control how accessible sequence information is to the cell as well as splicing patterns. These changes can be heritable even though they do not change the genome.

The researchers wanted to find out what epigenetic marks were enriched in IncRNA regions. What they discovered is that the retained introns in IncRNAs are associated with the marker H3K4me3. This marker has previously been found in regions of protein coding exons with high alternative splicing activity. 

In conclusion, RNAs are associated with nucleosome positioning patterns that are similar to those of protein coding regions. This means that IncRNA exons likely experience the same types of epigenetic regulation that protein coding regions do.

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Pinki Dey & John Mattick. High frequency of intron retention and clustered H3K4me3-marked nucleosomes in short first introns of human long non-coding RNAs. Epigenetics & Chromatin (2021). 

DOI: https://doi.org/10.1186/s13072-021-00419-2