Machine Learning Reveals Transcriptional Buffering in Rett Syndrome Nerve Cells

Researchers at The Hospital for Sick Children (SickKids) in the Dr. James Ellis Lab have published a study in Nature Communications detailing how nerve cells can compensate for genetic changes that cause Rett syndrome, a rare neurodevelopmental condition that results in the loss of motor and language skills in girls over time. Rett syndrome is caused by a genetic variation in the MECP2 gene located on the X chromosome, resulting in affected brain nerve cells expressing the wrong levels of over one thousand genes.

The team found that the nerve cells in Rett syndrome can partially compensate for these genetic changes through transcriptional buffering, a process where cells balance the total amount of RNA produced by proteins that bind RNA and shuttle it from the nucleus to the cytoplasm.

Using machine learning, the researchers found that transcriptional buffering only buffers about half of the genes in Rett syndrome, resulting in modest two-fold changes in RNA levels. By safeguarding the healthy levels of so many genes, transcriptional buffering acts as a defense against genetic variations that change RNA production, such as those seen in Rett syndrome.

The study is one of the first to combine measurements of both transcription and the breakdown of RNA molecules in human disease. The researchers used stem cells from a patient with Rett syndrome and employed a special type of RNA sequencing called RATESeq to directly measure how fast new RNA is made and broken down in cells. RATESeq allowed the researchers to see that changes in RNA stability drove transcriptional buffering in Rett syndrome nerve cells.

The study’s lead author, Dr. James Ellis, compared the process of making RNA in Rett syndrome to a novice driver struggling with jerky accelerations and screeching stops. In the human brain, transcriptional buffering acts as a “cruise control” system to maintain a constant speed and moderate these exaggerated movements.

The researchers note that a greater understanding of the buffering mechanism may help future investigations to use transcriptional buffering to help treat the effects of Rett syndrome. They also suggest that the molecular mechanism discovered in human cells may be important in regulating RNA levels in typical development.