Buffering of transcription rate by mRNA half-life is a conserved feature of Rett syndrome models

Transcriptional changes in Rett syndrome (RTT) are assumed to directly correlate with steady-state mRNA levels, but limited evidence in mice suggests that changes in transcription can be compensated by post-transcriptional regulation. We measure transcription rate and mRNA half-life changes in RTT patient neurons using RATEseq, and re-interpret nuclear and whole-cell RNAseq from Mecp2 mice. Genes are dysregulated by changing transcription rate or half-life and are buffered when both change. We utilized classifier models to predict the direction of transcription rate changes and find that combined frequencies of three dinucleotides are better predictors than CA and CG. MicroRNA and RNA-binding Protein (RBP) motifs are enriched in 3MODIFIER LETTER PRIMEUTRs of genes with half-life changes. Nuclear RBP motifs are enriched on buffered genes with increased transcription rate. We identify post-transcriptional mechanisms in humans and mice that alter half-life or buffer transcription rate changes when a transcriptional modulator gene is mutated in a neurodevelopmental disorder. Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the transcriptional modulator MECP2. Here, the authors measured transcription rate and mRNA half-life changes in RTT patient-derived neurons to show transcription rate buffered by mRNA half-life changes.

Automated summary

This study measured transcription rate and mRNA half-life changes in RTT patient-derived neurons and reinterpreted nuclear and whole-cell RNAseq from Mecp2 mice. The results showed that dysregulation of genes in RTT is caused by changes in transcription rate or half-life, but genes are buffered when both change. In addition, three dinucleotide frequencies were found to be better predictors of transcription rate changes than CA and CG. MicroRNA and RNA-binding Protein (RBP) motifs were enriched in the 3'UTRs of genes with half-life changes, while nuclear RBP motifs were enriched in buffered genes with increased transcription rate. The study revealed post-transcriptional mechanisms in neurodevelopmental disorders caused by mutations in transcriptional modulator genes.