Wrapped in genomic heterochromatin are elements similar to ancient viruses that could jump
Host defenses work to prevent “old viruses” from jumping, but, in cancers, cells lose multiple layers of “epigenetic” control, and this can lead to jumping awakening or “retrotransposition” of old viruses.
The ‘dark genome’ refers to the large number of DNA within the human genome and contains strings of repetitive DNA sequences. most of dark genome it is derived from transposable elements, which are invaders of the ancient genome, a minority of which can still replicate and jump to invade new genomic locations. The host’s defenses operate to prevent these transposable elements or “old viruses” from jumping out. Still, in cancers, cells lose multiple layers of ‘epigenetic’ control and this can lead to the awakening of jumping or ‘retrotranspose’ viruses. This jump to our genes can disrupt their function and cause disease.
How can research aimed at studying the function of the dark genome benefit us?
Cutting-edge research in this area will shed light on 1. New mutations that are linked to diseases like cancer and could be used as therapies, 2. Which parts of our genome could be used in cancer vaccines to direct immune responses to eliminate the tumor, and 3. How the dark genome contributes to the evolution of cancer.
Through an initial grant from the European Research Council, we have been studying the dark genome in early mouse development. Our goal is to understand which ancient viruses are turned on and off and how and what effect this has on host genes and cell fate. This research has provided new conceptual breakthroughs, which will pave the way for research and therapeutic applications in human cells. This article summarizes how ancient viruses that retain hopping activity to this day are regulated and how ancient viruses that are no longer mobile can be repurposed for the benefit of hosts as regulatory elements of our own genes.
How do we turn off jumping viruses and make them harmless?
In previous work, we discovered a critical host defense pathway involving TRIM28 and KRAB zinc finger proteins (KRAB-ZFP) that targets and inactivates transcription of ancient viruses. This defense pathway operates at the chromatin level by recruiting an enzyme known as SETDB1, which is a “chromatin writer” and establishes silent chromatin (heterochromatin) on the nucleosomes surrounding ancient viral DNA. SETDB1 does this by adding a modification to the histone tails of trimethylation at lysine nine at histone three (H3K9me3), an epigenetic mark associated with gene silencing. In our new studies, we have found that the TRIM28 pathway targets dangerous DNA sequences because they give ancient viruses the ability to jump. This ensures that old viruses that can jump are wrapped in heterochromatin and rendered harmless.
How do we select which ancient viruses to activate as gene regulatory elements?
Our recent work has also shed light on which copies of old viruses in the genome are reused by the host to serve as regulatory elements: during the retrotransposition process, old viruses copy or reverse transcribe their RNA genome into DNA to replicate and integrate into new sites within the genome. This process can be error prone and can lead to mutations and deletions of parts of your sequence along the way. In fact, our research shows that if they lose their jumping ability, they also lose vital sequences required for TRIM28 pathway targeting. This is because the TRIM28 pathway targets the same strings of sequences vital for viral replication (jumps). This indicates that old viral copies must lose their threat to be co-opted by the host as alternative promoters, enhancers, and noncoding RNAs.
How are these findings relevant to cancer?
As introduced at the beginning of this article, cancer represents a unique disease context in which multiple layers of host defenses are disrupted. This, in turn, can lead to a loss of epigenetic control of our genomic load of ancient viruses. This explains why recent research has highlighted an increase in the actual jumping of old viruses (of the LINE-1 type) through various human cancers. This hopping activity has been linked to causing various genetic alterations in cancers, including the mutation of tumor suppressor genes (which generally protect us against cancer). We hypothesize that jumping viruses also contribute to the evolution of cancer by creating greater genetic diversity. This then provides a platform from which groups of cancer cells (clones) with selective advantages can be developed, for example gaining the ability to evade destruction by the immune system. Further research will shed light on new molecular vulnerabilities that may be targeted to outwit cancer.