The expression of genes has to be very carefully controlled by cells; serious problems can arise when genes are expressed in the wrong places, at the wrong times, or at the wrong levels, for some examples. In the case of a gene called chromodomain helicase DNA binding protein 2 (CHD2), excessive expression can lead to a serious neurodevelopmental disease that causes intellectual delays, lack of speech and lack of movement in patients. Scientists have now identified an RNA molecule called CHASERR that helps regulate how much CHD2 protein is made. When CHASERR (CHD2 adjacent, suppressive regulatory RNA) is not functioning normally, it leads to the expression of abnormal levels of CHD2 protein.
The findings, which highlight the importance of non-coding regions of DNA, have been reported in the New England Journal of Medicine.
Only about two percent of the human genome codes for protein, and while the remainder was once simply ignored, scientists now know that there are many critical sequences in those non-coding genomic regions. Many long, non-coding RNAs are transcribed from the genome to serve a regulatory function in cells. This research has highlighted how important some of those non-coding sequences can be.
In this work, removing CHASERR was found to alter CHD2 expression. "We call CHD2 a ‘Goldilocks Gene,’ because both too little is bad and too much is also bad. There's no reason at all to think that this is an isolated case, but more likely that these long non-coding RNAs and non-coding regions are implicated more broadly across human disorders,” said corresponding study author Gemma Carvill, an assistant professor at Northwestern University Feinberg School of Medicine.
Previous work by Carvill and colleagues has shown that autism and epilepsy can arise when there are abnormally low levels of CHD2 protein. This work assessed the impact of too much CHD2 protein.
There were three patients involved in this study, who carry mutations that remove CHASERR, the lncRNA that affects CHD2 expression.
Carvill noted that altering CHASERR levels to produce the proper amount of CHD2 protein may offer a new treatment option for some patients.
“With three patients, we were able to finally classify this as a new disorder,” said co-senior study author Professor Anne O'Donnell-Luria, co-director of the Broad Center for Mendelian Genomics, among other appointments.
The study authors noted that this work may only be the beginning of studies that reveal how errors in non-coding RNAs may lead to human disease.
The parents of one patient in this study was able to have their child's genome sequenced, so he learned of her CHASERR deletion. Her father then set out to find researchers who investigate CHD2, and once he was connected to Carvill, the team began to study his daughter and two other patients who were identified after a global search.
Now, Carvill and colleagues want to look for ways to target these genomic problems with medications or gene therapy techniques.
Sources: Northwestern University, New England Journal of Medicine
