PRMT5 methylome profiling uncovers a direct link to splicing regulation in human acute myeloid leukemia

UID: 10514

Author(s): Radzisheuskaya, Aliaksandra*, Helin, Kristian* * MSK affiliated

Description: Summary from the GEO: "Protein arginine methyltransferase 5 (PRMT5) belongs to the class II arginine methyltransferases and catalyzes monomethylation and symmetrical dimethylation of arginines on proteins. It has recently emerged as a promising cancer drug target, and three PRMT5 inhibitors are currently in clinical trials for a range of malignancies. In this study, we aimed to further elucidate the role of PRMT5 in acute myeloid leukemia (AML). Using an enzymatic dead version of PRMT5 as well as a PRMT5-specific inhibitor, we demonstrated the requirement of the catalytic activity of PRMT5 for the survival of AML cells. By using multiplexed quantitative proteomics, we identified PRMT5 substrates and investigated their role in the survival of AML cells. We found that the function of the splicing regulator SRSF1 relies on its methylation by PRMT5. Consistent with this, we found that loss of PRMT5 led to changes in alternative splicing. This analysis revealed multiple affected essential genes, linking PRMT5 activity to its loss of function phenotype. Our results show that PRMT5 regulates binding of SRSF1 to mRNAs and proteins in leukemia and provide potential biomarkers for the treatment response to PRMT5 inhibitors.
RNA-sequencing and SRSF1 RIP-sequencing of THP-1 cells with and without PRMT5 knockdown (3 biological replicates, 6 days after transduciton)."

Subject of Study

Subject(s)

OncoTree Cancer Type(s)

Acute Myeloid Leukemia

Access via GEO
Plain text of processed sequence data and XSLX of differential expression and splicing of transcriptome.
Accession #: GSE129652

Access via SRA
RIP-Seq, RNA-Seq reads for 4 samples.
Accession #: SRP192029

Access via BioProject
Additional information about overall initiative.
Accession #: PRJNA532395
Access Restrictions: Free to All
Access Instructions: The NCBI Gene Expression Omnibus database provides open access to these files.
Associated Publications: Radzisheuskaya A, Shliaha P, Grinev V, et al. PRMT5 methylome profiling uncovers a direct link to splicing regulation in acute myeloid leukemia. Nature Structural and Molecular Biology. 2019; 26(11):999-1012.
Data Type: Genomic
Equipment Used: Illumina NextSeq 500
Dataset Format(s): Plain Text, SRA, XLSX
Dataset Size: 8.1 Mb (XLSX), 377.1 Kb (TXT), SRA broken up into files of 2.3 and 7.3 GB.

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