Principles of mRNA control by human PUM proteins elucidated from multimodal experiments and integrative data analysis

Area of Science:

• Molecular Biology
• Gene Regulation
• RNA Biology

Background:

• PUM1 and PUM2 are human PUF-family proteins that regulate gene expression posttranscriptionally.
• They bind to PUM recognition elements (PREs) in the 3 -untranslated regions (UTRs) of target mRNAs.
• Previous methods could not distinguish between transcriptional changes and RNA decay rates.

Purpose of the Study:

• To determine whether human PUM proteins regulate gene expression by altering transcription or RNA stability.
• To identify the precise binding preferences of PUM1 and PUM2.
• To develop a predictive model for PUM protein-mediated RNA regulation.

Main Methods:

• Metabolic labeling was used to measure changes in RNA turnover upon PUM1/2 depletion.
• In vitro selection workflows were employed to identify PUM1 and PUM2 binding preferences.
• Machine learning models were trained using a developed "rulebook" of functional PRE features.

Main Results:

• Human PUM proteins regulate gene expression almost exclusively by modulating RNA stability.
• The study precisely identified the binding preferences of PUM1 and PUM2.
• A predictive model was developed that accurately identifies functional RNA targets of PUM proteins.

Conclusions:

• PUM1 and PUM2 are key regulators of mRNA stability in humans.
• Understanding PUM protein binding preferences allows for accurate prediction of their regulatory roles.
• This work provides a framework for predicting functional RNA-protein interactions.