Study unravels gene expression control mechanism with immunity and cancer implications

Despite alternative polyadenylation (APA)—the RNA processing mechanism that regulates gene expression by generating different ends on RNA transcripts of the same gene—affecting a larger part of human genes, the importance of APA was not well understood.

Wistar’s Dr Bin Tian. Image Credit: The Wistar Institute.

However, research led by The Wistar Institute unraveled the vital function of APA in enabling some mRNAs to reach specific sites of protein synthesis and revealed that sequence, length, and structural properties could define the destination (and fate) of mRNAs within the cell.

The study results have been published online in the Cell Reports journal and elucidate the consequences of APA that might represent a paradigm shift in the mRNA metabolism field.

The prevalent occurrence of APA has been identified through genomic and bioinformatic approaches at the lab of Bin Tian, Ph.D., for the first time. Tian is a professor and co-leader of the Gene Expression & Regulation Program at The Wistar Institute Cancer Center. He is also the senior author of the study.

After gene transcription, messenger RNAs are chemically transformed into mature RNA molecules that leave the nucleus and carry out their functions. One such modification is polyadenylation, which restricts RNA degradation and promotes its change into protein.

Using APA, a gene can be polyadenylated at several sites, leading to mRNAs with various coding sequences and/or regulatory regions (3′untranslated regions or 3′UTRs) called isoforms.

Transcripts that encode the same protein can end up with different fates in the cell due to different 3′UTRs that harbor regulatory elements for mRNA metabolism. This significantly heightens the complexity of the human genome, so that fewer genes are required to encode all the proteins a cell requires.

Tian and his associates applied functional genomics methods to assess the distribution of the APA isoforms in mouse cells. Machine learning approaches and bioinformatic analysis unraveled that APA, through modulation of mRNA 3′UTRs, affects the link between mRNAs and the endoplasmic reticulum (ER), a network of tubes that develop, package, and transport proteins.

The researchers called this mechanism translation-independent ER association (TiERA) and discovered that certain mRNAs feature specific sequences and structures that ascertain their potential to undergo APA and eventually associate with the ER.

When mRNAs leave the nucleus and move to the cytoplasm, they need to be properly directed to reach the appropriate site of protein translation. The cytoplasm is a huge space for an RNA molecule: For comparison, imagine entering a baseball stadium and needing directions to reach your seat.”

Bin Tian, PhD, Study Senior Author, Professor, and Co-leader, Gene Expression & Regulation Program, The Wistar Institute Cancer Center

The researchers discovered that mRNAs with higher TiERA tend to encode signaling proteins, helping cells to communicate with each other by receiving, sending, and processing signals in response to environmental changes.

The researchers further state that APA makes this process highly efficient by anchoring some mRNA isoforms with the ER in particular cellular locations where vital signaling events occur.

According to our model, the ER would serve as a scaffold to keep proteins ‘on hand’ where they are most needed. This would provide a platform for signaling events to happen effectively at the right place in the cell.”

Bin Tian, PhD, Study Senior Author, Professor, and Co-leader, Gene Expression & Regulation Program, The Wistar Institute Cancer Center