TED-Seq Identifies the Dynamics of Poly(A) Length during ER Stress

Area of Science:

• Molecular Biology
• Genetics
• Cell Biology

Background:

• Post-transcriptional RNA processing, particularly poly(A) tail dynamics, is vital for gene expression control during cellular stress responses.
• The precise global roles of poly(A) tail lengths in response to cellular stress, however, remain incompletely understood.

Purpose of the Study:

• To investigate the global roles of poly(A)-tail lengths in response to endoplasmic reticulum (ER) stress.
• To develop and apply an efficient method for transcriptome-wide profiling of poly(A) tail lengths.

Main Methods:

• Development of tail-end displacement sequencing (TED-seq) for efficient transcriptome-wide poly(A) length profiling.
• Application of TED-seq to human cells undergoing ER stress.

Main Results:

• ER stress led to increased poly(A) tail lengths for specific mRNAs, including key ER stress regulators like XBP1, DDIT3, and HSPA5.
• mRNAs with elongated poly(A) tails exhibited both translational de-repression and enhanced stability.
• mRNAs localized within stress-induced RNA granules possessed shorter poly(A) tails compared to those in the cytoplasm, suggesting compartmentalized RNA processing.

Conclusions:

• TED-seq effectively reveals dynamic poly(A) length regulation in response to ER stress.
• Changes in poly(A) tail length during ER stress have significant implications for both mRNA translation and turnover.
• RNA processing is compartmentalized within the cell, as evidenced by differential poly(A) tail lengths in cytoplasmic versus RNA granule fractions.