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Transcriptional buffering safeguards cells in Rett syndrome

Written by Charlotte Harrison, Science Writer.

A study published in Nature Communications offers new insight into the mechanisms involved in the neurodevelopmental disorder Rett syndrome.

Rett syndrome is caused by a genetic variation in MECP2 (methyl CpG-binding protein 2), which regulates transcription globally. This change causes affected nerve cells in the brain to express the wrong levels of more than one thousand genes.

Researchers from Canada’s Hospital for Sick Children show that, in Rett syndrome, nerve cells help compensate for these genetic changes through a process called transcriptional buffering – a balancing act between mRNA synthesis and degradation.

Balancing act

For their studies, the researchers used neuronal cells derived from a patient with Rett syndrome and mouse models. They performed RATESeq, an equilibrium-based sequencing method that uses in vivo metabolic labelling of RNA to measure RNA synthesis and degradation.

The researchers showed that when too much or too little RNA is produced in Rett-syndrome nerve cells, the stability of the RNA changes. To compensate for these changes in stability, the cells use transcriptional buffering to balance the total amount of RNA present.  

Using machine learning, the researchers showed that transcriptional buffering uses RNA-binding proteins to bind RNA and shuttle it from the nucleus to the cytoplasm, where the proteins control RNA breakdown. Around half of the genes are transcriptionally buffered in Rett-syndrome cells, but nevertheless this led to two-fold changes in RNA levels. 

Cruise control

Overall, the authors  propose that transcription rate increases in MECP2 neurons are subject to surveillance by RNA binding proteins that post-transcriptionally regulate RNA half-life.

 “For people with Rett syndrome, the process of making RNA is like a novice driver in a car struggling with jerky accelerations and screeching stops,” said lead author James Ellis in a press release. “One way to moderate these exaggerated movements is by using a ‘cruise control’ system that can maintain a constant speed. This is done in the human brain by transcriptional buffering.” 

The researchers note that this improved understanding of transcriptional buffering may not only help endeavours to treat Rett syndrome, but also aids studies investigating the role of RNA regulation in typical neuronal development.