A team led by scientists at the UNC School of Medicine identified a molecule called microRNA-29 as a powerful controller of brain maturation. Deleting microRNA-29 causes problems very similar to those seen in autism, epilepsy, and other neurodevelopmental conditions, according to a news release from the university.
The results, published in Cell Reports, illuminate a process in the normal maturation of the brain and point to the possibility that disrupting this process could contribute to multiple human brain diseases.
“We think abnormalities in microRNA-29 activity are likely to be a common theme in neurodevelopmental disorders and even in ordinary behavioral differences in individuals,” said Mohanish Deshmukh, PhD, Professor in the UNC Department of Cell Biology & Physiology and member of the UNC Neuroscience Center. “Our work suggests that boosting levels of miR-29, perhaps even by delivering it directly, could lead to a therapeutic strategy for neurodevelopmental disorders, such as autism.”
MicroRNAs are short stretches of ribonucleic acid inside cells that regulate gene expression. Each microRNA, or miR, can bind directly to an RNA transcript from certain other genes, preventing it from being translated into a protein. MiRNAs thus effectively serve as inhibitors of gene activity, and the typical microRNA regulates multiple genes in this way so that genetic information is not overexpressed. These essential regulators have been intensively researched only in the past two decades. Therefore, much remains to be discovered about their roles in health and disease.
Deshmukh and colleagues set out to find microRNAs involved in the maturation of the brain after birth, a phase that in humans includes approximately the first 20 years of life. Many genes are much more active when miR-29 is no longer there to block their activity. But the scientists unexpectedly found a large set of genes – associated with brain cells – that were less active in miR-29’s absence.
One of the target genes that miR-29 normally blocks is a gene that encodes for an enzyme called DNMT3A. This enzyme places special chemical modifications called CH-methylations onto DNA to silence genes in the vicinity. The activity of the gene for DNMT3A normally rises at birth, then sharply declines several weeks later. The scientists found that miR-29, which blocks DNMT3A, is what normally forces this sharp decline.
Thus, in brains lacking miR-29, DNMT3A is not suppressed and the CH-methylation process continues abnormally – and many brain cell genes that should become active continue to be suppressed instead. Some of these genes, and the gene for DNMT3A itself, have been found to be missing or mutated in individuals with neurodevelopmental disorders such as autism, epilepsy, and schizophrenia.
The findings highlight and clarify what seems likely to be a crucial process in shaping the brain late in its development: the switching-off of DNMT3A to free up many genes that are meant to be more active in the adult brain.
