Epigenetics and RNA Metabolism in Human Diseases
Quantitative Biology
To produce a protein, a cell must first make a messenger RNA (mRNA) containing the open reading frame that will be read by ribosomes. But producing this mature mRNA requires much more transcription than just the protein-coding sequence.
First, the gene needs to be activated, which involves transcription at the promoter and at distant regulatory elements called enhancers. These events generate non-coding RNAs, respectively PROMPTs (Promoter Upstream Transcripts) and eRNAs (enhancer RNAs).
Transcription of the gene itself produces an RNA that includes both exons (the coding regions) and introns—large stretches of sequence that do not contribute to the final protein and must be removed through splicing. This splicing process produces additional non-coding RNA fragments.
Finally, once the polymerase reaches the end of the gene, it needs to stop. But transcription termination is not always efficient—RNA polymerase II, a massive machine of over 500 kDa, often continues for kilobases beyond the gene’s end. This produces another class of non-coding RNAs called DOGs (Downstream of Genes).
All these RNAs—PROMPTs, eRNAs, excised introns, DOGs—are what we call perigenic RNAs: RNAs produced around genes. They are usually very unstable and quickly degraded, which is why they are rarely seen in standard experiments. But in certain diseases, some of them begin to accumulate.
For example:
- In infections by influenza or SARS-CoV-2, cells accumulate DOGs.
- In ulcerative colitis, splicing is defective, and parts of introns remain in the mature mRNA.
So, what are these RNAs? Are they just bystanders, accumulating because the machinery that normally removes them is broken? Or could they have an actual function?
In the lab, we favor the second hypothesis. We think that these RNAs play a role in the innate immune response—by forming double-stranded RNAs (dsRNAs), which are the molecular signature of viral infection, or by occasionally encoding micropeptides, tiny proteins produced from so-called “non-coding” RNAs.
But their accumulation can also be problematic. If produced in excess or for too long, these RNAs may trigger chronic inflammation or autoimmunity.
Why Are Perigenic RNAs So Special?
One reason lies in their origin. Non-coding regions of the genome have been under less selective pressure and have been colonized by transposable elements (TEs)—ancient mobile sequences that duplicated and inserted themselves throughout the genome.
Though most of these TEs are now inactive, they’ve left behind repetitive DNA sequences inserted in both orientations. When transcribed, these give rise to inverted repeats that fold into double-stranded RNA (dsRNA) structures.
Some of these structures make it out of the nucleus and into the cytoplasm—where they don’t belong. Normally, only viral RNAs form long dsRNA in the cytoplasm. So, when these endogenous dsRNAs appear there, the dsRNA-sensors mistake them for molecules from viral invaders and trigger inflammation.
This can be useful—especially against viruses that camouflage their dsRNA, like influenza. In such cases, perigenic RNAs may serve as internal alarms, warning the immune system that the cell is infected.
But in the absence of infection, due to a genetic or epigenetic defect, this same signal can lead to inappropriate inflammation, pain, and autoimmune disease.
TEs can also retain open reading frames, or fragments of them, from their days as mobile elements. If these sequences are positioned just right, they can be translated into micropeptides. We know very little about their function, but they are another possible layer of biological activity associated with perigenic RNAs.
ONGOING PROJECTS
1- DOGs in SARS-CoV-2 Infection
SARS-CoV-2 infection activates a wide range of immune response genes. At many of these genes, transcription fails to terminate properly, leading to the accumulation of DOGs.
This might be a viral strategy—keeping RNA polymerase stuck at the end of the gene to reduce production of defense proteins.
Or it might be a host strategy—generating extra dsRNA to amplify antiviral signaling.
We are investigating how DOGs contribute to the inflammation associated with COVID-19.
2- TE-Derived RNAs, HP1, and Hepatocellular Carcinoma
One family of proteins that helps recognize repeat-rich RNAs is HP1 (heterochromatin protein 1), which exists in α, β, and γ forms. We’ve shown that HP1 helps cells distinguish exons from introns, and that it also participates in recognizing and degrading repeat-containing RNAs—a function already described in yeast.
In a subtype of hepatocellular carcinoma (HCC), HP1 expression is reduced, resulting in the accumulation of enhancer-derived RNAs. These tumors show higher inflammation, but are also less deadly.
3– Elongation Defects in Multiple Sclerosis
Multiple sclerosis (MS) is a debilitating disease that targets the myelin sheath of nerves in the central nervous system. While its immune aspects are well described, the molecular triggers remain unclear.
Interestingly, many MS patients express endogenous retroviruses—a form of TE—suggesting that perigenic RNA regulation may be altered.
We found that in a subset of MS patients, especially those in progressive phases, RNA polymerase II fails to pause and mature properly at promoters. Instead, it begins transcribing prematurely.
This leads to:
- Overexpression of short, inflammatory genes
- Underexpression of long, structural genes
- Accumulation of perigenic RNAs, particularly just downstream of first exons
We are currently exploring the functional role of these aberrant transcripts in MS pathology.
Group Domain: Quantitative
Members
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Ismail Bouargalne
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Eric Batsché
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Christophe Rachez
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Christian Muchardt
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