How Shutting Down DNA Methylation Affects the “Dark Matter” in Our Genome

Along the vast stretches of molecules that make up our DNA, only a small portion (about 3%) consists of genes, the essential building blocks or our bodies. The rest has been considered dark matter, as it appears to serve little to no biological purpose. Out of this area, the most substantial bulk is comprised of mobile genetic elements that scientists call transposons or transposable elements (TEs). Throughout evolution, these TEs have colonized our genome by basically copying and pasting themselves several times – randomly adding snippets of code here and there to our genetic sequence.

Almost always, transposons are a threat to genomic stability; therefore, most will be epigenetically silenced during the early stages of development via DNA methylation. It’s believed that their activity, if initiated, might cause a serious disorder or possibly death. But little is truly known about these dark elements. For a long time, scientists have been more preoccupied studying genes that code proteins for cells, dismissing TEs as junk DNA.  But that viewpoint is slowly changing, and newer studies are interested in learning more about the larger half of our genome.

Now for the first time, scientists from Sweden and Germany have undertaken a project to observe what happens to transposons when DNA methylation is lost in human cells. Their findings were recently published in July issue of Nature Communications.

Transposons are often referred to as the “jumping genes” because they can bounce around in our genetic material and insert themselves wherever they want. For millions of years, these jumping genes moved around quite a lot. Their random insertions either negatively or positively impacted our genome. Beneficial modifications were passed on, and detrimental ones were usually lost within a single generation. Over time, the majority of these transposons became immobilized to prevent any havoc from occurring, securing our genetic code as it is today. But some are still active, and every so often they can be traced to the cause of a disease or malfunction. For instance, certain colon cancers and blood disorders like hemophilia involve misplaced TEs.

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DNA methylation is a chemical modification that can turn parts of our genome off. In healthy tissue, nearly all transposons are transcriptionally repressed by DNA methylation. The formation of this mechanism, which occurs during early embryo development, is believed to be necessary for silencing complexes that repress the transcription of transposons in somatic cells.

According to Lund University professor Johan Jakobsson who led the study, occasionally DNA methylation can become disrupted, and previous research has demonstrated this to be crucial in some cancers and neuropsychiatric diseases. He stated, “DNA methylation is used as a target for therapy in certain cancer types, such as leukemia, but we still lack knowledge about why this is effective and why it only works for certain types of cancer.”

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While the role of transposons in our DNA isn’t fully understood, the researchers hypothesized that DNA methylation is the mechanism responsible for silencing unused segments of the genome. Only now, with the discovery of CRISPR has it been possible to finally study what happens when this important process is taken out of a cell. Here the researchers used the CRISPR/Cas9 method to precisely remove methylation in human neural stem cells.

What they found was that a loss of DNA methylation resulted in the active transcription of the evolutionarily young transposon, LINE-1 (short for “long interspersed element 1). This was also accompanied by the acquisition of active histone mark H3K27ac.

The results surprised Jakobsson and his team. He said, “If you shut down DNA methylation in mouse cells, they don’t survive, but when DNA methylation was shut down in the human nerve stem cells, they survived and a specific set of transposons were activated.”  In turn, they saw that these transposons affected many genes that are important in the development of the nerve cells.

The results from this study offer up an entirely new understanding of how DNA methylation impacts the genome, in particular, how its loss affects various diseases. This initial study was conducted on cultured cells in a lab, but the researchers hope to move forward and investigate how shutting down methylation affects cancer cells impacted by this mechanism.

Reference: Lund University. “Shedding light on darker parts of our genetic heritage.” July 19, 2019.

Source: Marie E Jönsson, et al. Activation of neuronal genes via LINE-1 elements upon global DNA demethylation in human neural progenitors. Nature Communications, 2019; 10 (1).

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