Transcriptional boosting and buffering during neurodevelopment by shifts in mRNA instability

The contribution of mRNA half-life is commonly overlooked when examining changes in mRNA abundance during development. mRNA levels are regulated by transcription rate or mRNA half-life, but combinations of both could boost or buffer the final steady-state. We measured transcription rate and mRNA half-life changes during human induced pluripotent stem cell (iPSC)-derived neuronal development using RATE-seq. The most prevalent mode of gene regulation during transitions to neuronal progenitors and neurons was transcriptional buffering. Less prevalent modes consisted of transcriptional boosting events, transcription rate only shifts, or mRNA half-life only shifts. Buffered and novel boosted gene sets were enriched in RNA-binding protein (RBP) motifs and microRNA sites. Global mRNA half-life decreased two-fold in neurons. microRNA copy number per cell increased during neurodevelopment coincident with destabilization of a subset of short isoforms that contributed to increased average 3'UTR length. Our findings identify mRNA instability mechanisms that regulate transcript levels and 3'UTR isoform abundance, and provide a precedent for transcriptional boosting or buffering during development of other human tissues.