PRMT5-mediated SRSF1 methylation promotes virus-positive Merkel cell carcinoma tumorigenesis by increasing Tip60 exon inclusion [PacBio Sequel IIe]
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ABSTRACT:
PROVIDER: PRJNA1228633 | ENA |
REPOSITORIES: ENA
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Project description:Protein Arginine Methyltransferase 5 (PRMT5) is a key regulator of gene expression and RNA splicing, with its therapeutic potential demonstrated through synthetic lethality in MTAP-deleted cancers. Emerging evidence also suggests that MYC-driven or p53 wild-type tumors may be more sensitive to PRMT5 inhibition, though the underlying mechanisms remain unclear. Virus-positive Merkel cell carcinoma (MCC) serves as an ideal model to explore this question, as it is driven by the MYC paralog MYCL, and most virus-positive MCCs retain wild-type p53. In this study, we investigated PRMT5’s impact on the Tip60-EP400 complex, given MCC’s reliance on the interaction between MYCL and this complex. We used second-generation sequencing (Illumina) to characterize PRMT5-mediated bulk gene expression and long-read RNA sequencing (PacBio Iso-Seq) to analyze PRMT5-mediated alternative splicing. The mechanism underlying PRMT5 deficiency's selective impact on specific splice sites while leaving others unaffected remains unclear. Our findings suggest that PRMT5-mediated methylation of SRSF1 enhances its recruitment to m6A-modified RNA, ensuring proper splicing of Tip60 and maintaining Tip60-EP400 activity. In contrast, PRMT5 inhibition disrupts this recruitment, leading to widespread splicing defects, including both exon skipping and intron retention. These results provide new insights into PRMT5’s role in splicing regulation in cancer cells and may have broader implications for targeting splicing dysregulation in MYC-driven cancers.
2025-08-20 | GSE290569 | GEO
Project description:Protein Arginine Methyltransferase 5 (PRMT5) is a key regulator of gene expression and RNA splicing, with its therapeutic potential demonstrated through synthetic lethality in MTAP-deleted cancers. Emerging evidence also suggests that MYC-driven or p53 wild-type tumors may be more sensitive to PRMT5 inhibition, though the underlying mechanisms remain unclear. Virus-positive Merkel cell carcinoma (MCC) serves as an ideal model to explore this question, as it is driven by the MYC paralog MYCL, and most virus-positive MCCs retain wild-type p53. In this study, we investigated PRMT5’s impact on the Tip60-EP400 complex, given MCC’s reliance on the interaction between MYCL and this complex. We used second-generation sequencing (Illumina) to characterize PRMT5-mediated bulk gene expression and long-read RNA sequencing (PacBio Iso-Seq) to analyze PRMT5-mediated alternative splicing. The mechanism underlying PRMT5 deficiency's selective impact on specific splice sites while leaving others unaffected remains unclear. Our findings suggest that PRMT5-mediated methylation of SRSF1 enhances its recruitment to m6A-modified RNA, ensuring proper splicing of Tip60 and maintaining Tip60-EP400 activity. In contrast, PRMT5 inhibition disrupts this recruitment, leading to widespread splicing defects, including both exon skipping and intron retention. These results provide new insights into PRMT5’s role in splicing regulation in cancer cells and may have broader implications for targeting splicing dysregulation in MYC-driven cancers.
2025-08-20 | GSE290105 | GEO
Project description:PRMT5-mediated SRSF1 methylation promotes virus-positive Merkel cell carcinoma tumorigenesis by increasing Tip60 exon inclusion
| PRJNA1228975 | ENA
Project description:PRMT5-mediated SRSF1 methylation promotes virus-positive Merkel cell carcinoma tumorigenesis by increasing Tip60 exon inclusion [JNJvsDMSO_raw]
| PRJNA1226215 | ENA
Project description:This SuperSeries is composed of the SubSeries listed below.
2025-08-20 | GSE290609 | GEO
Project description: Not available
| S-EPMC12373721 | biostudies-literature
Project description:PRMT1 is highly expressed in breast tumors, and has been suggested to play a vital role in breast tumorigenesis, but the underlying molecular mechanisms remain to be fully characterized. Here, we reveal that PRMT1 exhibits a wide-spreading role in RNA alternative splicing based on transcriptome analysis, with a preference for exon inclusion in a large cohort of oncogenic genes. Profiling PRMT1 methylome reveals that the arginine/serine-rich splicing factor SRSF1 is heavily arginine-methylated by PRMT1, which is critical for SRSF1 phosphorylation, SRSF1 binding with RNA, and PRMT1-induced exon inclusion. In breast tumors, the overexpression of PRMT1 is associated with high levels of SRSF1 arginine methylation and aberrant exon inclusion in those oncogenic genes. Accordingly, PRMT1-mediated SRSF1 methylation and exon inclusion events are found to be critical for the malignant behaviors of breast cancer cells. Furthermore, we identified and characterized a selective PRMT1 inhibitor iPRMT1, which is potent in inhibiting PRMT1-mediated SRSF1 methylation and exon inclusion events, and breast cancer cell growth both in vitro and in vivo. Combination treatment with iPRMT1 and inhibitor targeting SRSF1 phosphorylation, SPHINX31 or SRPIN340, exhibits synergistic effects on suppressing breast cancer cell growth, strengthening the cross-talk between arginine methylation and phosphorylation in SRSF1. In conclusion, our data uncover a key mechanism underlying PRMT1-mediated gene alternative splicing, demonstrating targeting PRMT1 has great potential to treat breast cancer in clinic.
2023-10-02 | GSE212049 | GEO
Project description:The Tip60 (also known as Kat5) lysine acetyltransferase functions broadly as a transcriptional co-activator that acetylates histones. In contrast, Tip60 functions in embryonic stem cells (ESCs) both to silence genes that promote differentiation and to activate genes required for proliferation. The mechanism by which Tip60 functions as a repressor is unknown. Here we show that the class II histone deacetylase Hdac6 co-purifies with Tip60-p400 complex from ESCs and is necessary for complete silencing of most differentiation genes targeted by Tip60. In contrast to differentiated cells, where Hdac6 is mainly cytoplasmic and does not interact with Tip60, Hdac6 is largely nuclear in ESCs and neural stem cells (NSCs) and interacts with Tip60-p400 in both cell types. Hdac6 is enriched at promoters bound by Tip60-p400 in ESCs, but while Tip60 binds on both sides of transcription start sites (TSSs), Hdac6 binding overlaps with only the downstream Tip60 peak. Surprisingly, Hdac6 does not deacetylate histones at these sites, but rather is required for Tip60 binding. These data suggest that nuclear exclusion of Hdac6 during differentiation plays a major role in modulation of Tip60-p400 function. We determined the genome-wide localization of Tip60 and Hdac6 in mouse ES cells, and examined genomic binding profiles of Tip60 and Hdac6 upon indicated knockdown by ChIP-seq. We examined genomic binding profiles of p400 upon indicated knockdown by ChIP-seq.
2013-11-20 | E-GEOD-42209 | biostudies-arrayexpress
Project description:Genome-wide mapping of TIP60 complex subunits in K562 cells. The objectives of this study are to describe TIP60 genome wide localization, confirm MBTD1 co-localization with already known unique subunits and observe the impact of MBTD1 on TIP60 complex targeting to chromatin. The TIP60 acetyltransferase complex is a key regulator of genome expression and stability. Here, we identified MBTD1 as a new stable subunit of the complex and revealed interesting insights about TIP60 function during the repair of DNA double strand breaks. MBTD1 binds H4K20me1/2, helping TIP60 association to specific promoters but also the DNA repair process by homologous recombination. While pro-end joining factor 53BP1 engages chromatin through simultaneous binding of H4K20me2 and H2AK15ub, TIP60 regulates the resolution of 53BP1 foci after DNA damage through a related bivalent mechanism. MBTD1 competes with 53BP1 for the H4K20me2 mark, affecting its retention at the break cooperatively with H4 acetylation by TIP60. In addition, we show that H2AK15ub deposition by RNF168 inhibits chromatin acetylation by TIP60, whereas H2AK15 can also be acetylated by TIP60 in vivo, therefore blocking its ubiquitylation. Altogether, these results uncover an intricate mechanism orchestrated by the TIP60 complex to regulate 53BP1-dependent repair pathway selection, through incompatible bivalent binding/action on chromatin.
2016-04-30 | GSE69645 | GEO