Monday, June 19, 2017

A Lack of 'Editing' in The Brain Could Be What's Driving The Most Aggressive Tumours

Brain cancer is often a devastating diagnosis, and scientists have been hunting for mechanisms that could explain the sources of brain tumours, with hopes to also find something that could prevent them.

Now a new study has peered into the mechanisms of gene expression in the brain, and found that tissue samples from brain cancer patients show a lack of microRNA editing. This means we might one day find a way to use gene editing to slow down the progression of the disease.

MicroRNAs are short bits of RNA that don't code for proteins, but are still important for regulating gene expression. In fact, these molecules might be responsible for fine-tuning as much as 30 percent of all protein-encoding genes in mammals.

This fine-tuning happens through various changes to the RNA molecule, and this process is called 'editing'. Studies have shown that editing "changes the information encoded by the genome and adds complexity to the gene regulatory networks".

A common type of microRNA editing happens when one of its components, adenosine, is changed to a different one, inosine, lending the name 'A-to-I editing'.

Researchers know that A-to-I editing is a crucial process needed for normal functioning of the organism, especially when it comes to cell development and homeostasis.

Problems with microRNA editing, which lead to changes in gene expression, have already been linked to several types of cancer, including a type of brain cancer called glioma.

Now scientists have looked into the mechanisms behind microRNA editing in human brain tissue samples, looking specifically at the frontal cortex and corpus callosum, along with tumour samples of glioblastoma multiforme, a highly aggressive type of brain cancer.

The team found that brain tumour samples had significantly lower levels of A-to-I editing, while in healthy brains this process happens much more regularly, even in comparison to other types of tissue in the human body.

"What precisely is happening, we can't say, but with altered levels and positions of these editing events, cellular output can be significantly altered which we see in case of cancers," says lead researcher Arijit Mukhopadhyay from the CSIR-Institute of Genomics and Integrative Biology in India.

In other words, it looks like if microRNA editing goes off the rails and doesn't rearrange its components just so, it can lead to all kinds of genetic changes which in turn affect how the brain cells grow - sometimes for the worst.

Cancer happens when cells start dividing out of control and take over, so this new finding is an important step towards establishing what exactly goes wrong at the biochemical level when a brain tumour starts to form.

"[W]e have been able to show that in both healthy and diseased state, microRNA editing is an important layer of information with specific sequence and structural preferences – especially in the human brain," the team writes in the paper.

Scientists say they now need more research to further establish what happens in the brain to derail editing in a way that can lead to tumours. Conversely, they also hope to identify specific microRNA types that could protect us from cancer by suppressing tumour formation.

Armed with this knowledge, researchers could one day even use gene editing techniques like CRISPR to potentially fix the microRNA editing problems.

If this method can prevent the changes in cells that lead to cancer, it might be a way to prevent tumours from growing in the first place.

Early stress ups depression risk by permanently changing DNA

Beware! A study has revealed that individuals, who experience childhood stress and trauma, are at increased risk of depression by permanently changing their Deoxyribonucleic Acid (DNA). According to researchers, early life stress encodes lifelong susceptibility to stress through long-lasting transcriptional programming in a brain reward region implicated in mood and depression. The study focuses on epigenetics – a study of changes in the action of genes caused not by changes in DNA code we inherit from our parents, but instead by molecules that regulate when, where and to what degree our genetic material is activated. The function of transcription factors are specialised proteins that bind to specific DNA sequences in our genes and either encourage or shut down the expression of a given gene. Study’s lead investigator Catherine Pena said that the work identifies a molecular basis for stress during a sensitive developmental window that programs a mouse’s response to stress in adulthood. “We discovered that disrupting maternal care of mice produces changes in levels of hundreds of genes in the Ventral Tegmental Area (VTA), neurons located close to the midline on the floor of the midbrain, that primes this brain region to be in a depression-like state, even before we detect behavioural changes.

Essentially, this brain region encodes a lifelong, latent susceptibility to depression that is revealed only after encountering additional stress,” Peña added.

The investigators identified a role for the developmental transcription factor orthodenticle homeobox 2 (Otx2) as a master regulator of these enduring gene changes. The team showed that baby mice that were stressed in a sensitive period (from postnatal day 10-20) had suppressed Otx2 in the VTA. While Otx2 levels ultimately recovered by adulthood, the suppression had already set in motion gene alterations that lasted into adulthood, indicating that early life stress disrupts age-specific developmental programming orchestrated by Otx2. To test the prediction that Otx2 was actually responsible for the stress sensitivity, the team developed viral tools that were used to either increase or decrease Otx2 levels. They found that suppression of Otx2 early in life was both necessary and sufficient for increased susceptibility to adult stress. Senior investigator of the study Eric J. Nestler said that this mouse paradigm will be useful for understanding the molecular correlates of increased risk of depression resulting from early life stress and could pave the way to look for such sensitive windows in human studies. The study is published in the journal Science.