Productive mRNA Chromatin Escape is Promoted by PRMT5 Methylation of SNRPB

Area of Science:

• Molecular Biology
• Gene Regulation
• Epigenetics

Background:

• Protein Arginine Methyltransferase 5 (PRMT5) is known to regulate RNA splicing and transcription via symmetric dimethylation.
• The precise mechanism linking PRMT5's splicing regulation to transcriptional output has remained unclear.

Purpose of the Study:

• To elucidate the mechanism by which PRMT5 couples RNA splicing to transcriptional output.
• To identify and characterize a novel class of mRNAs regulated by PRMT5.

Main Methods:

• Nascent and total transcriptomics
• Spike-in controlled fractionated cell transcriptomics
• Total and fractionated cell proteomics
• PRMT5 inhibition and knockdown studies
• Arginine-mutant SNRPB studies

Main Results:

• PRMT5 activity promotes the chromatin escape of a novel class of mRNAs termed Genomically Retained Incompletely Processed Polyadenylated Transcripts (GRIPPs).
• PRMT5 inhibition or pICln knockdown causes mRNA, SNRPB, and SNRPD3 proteins to be detained on chromatin.
• Chromatin-trapped transcripts exhibit slower splicing and are enriched in detained introns.
• Arginine methylation of snRNPs is crucial for their interaction with chromatin and RNA.

Conclusions:

• PRMT5 plays a major role in controlling transcript processing and splicing completion.
• This processing and splicing control by PRMT5 is essential for promoting chromatin escape and nuclear export of specific mRNA classes.
• PRMT5-mediated regulation impacts the coupling of splicing to transcriptional output and gene expression.