Transcriptional neighborhoods regulate transcript isoform lengths and expression levels

Area of Science:

• Synthetic biology
• Genomics
• Molecular biology

Background:

• Gene sequence and regulatory regions influence RNA transcript isoform expression.
• Genetic context, including the adjacent transcriptional environment, also affects transcript isoform expression levels and boundaries.
• Understanding sequence-independent effects is crucial for precise synthetic biology applications.

Purpose of the Study:

• To systematically disentangle the effects of gene sequence and genetic context on RNA transcript isoform expression.
• To identify features of transcriptional context that influence gene expression and transcript boundaries.
• To engineer a synthetic circuit leveraging positional context for transcript length control.

Main Methods:

• Creation of synthetic yeast strains with stochastically repositioned genes.
• Profiling of 120 million full-length transcript molecules across 612 genomic perturbations.
• Bioinformatic analysis to identify predictive features of transcriptional context.

Main Results:

• Observed sequence-independent alterations in gene expression levels and transcript isoform boundaries.
• Demonstrated that neighboring transcription significantly influences these alterations.
• Identified specific transcriptional context features capable of predicting these expression changes.

Conclusions:

• Positional context plays a significant role in regulating gene expression and transcript isoform boundaries, independent of sequence features.
• Transcriptional context can be leveraged as a predictable element in synthetic genome engineering.
• This work provides a foundation for designing more sophisticated synthetic biological systems with precise transcriptional control.