ZMAT2 condensates regulate the alternative splicing of TRIM28 to reduce cellular ROS accumulation, thereby promoting the proliferation of HCC cells
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ABSTRACT:
SUBMITTER: Zhu Y
PROVIDER: S-EPMC11337747 | biostudies-literature | 2024 Jan
REPOSITORIES: biostudies-literature
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Project description:SRRM2 is a nuclear-speckle marker containing multiple disordered domains, whose dysfunction is associated with several human diseases. Using mainly EGFP-SRRM2 knock-in HEK293T cells, we show that SRRM2 forms biomolecular condensates satisfying most hallmarks of liquid-liquid phase separation, including spherical shape, dynamic rearrangement, coalescence and concentration dependence supported by in vitro experiments. Live-cell imaging shows that SRRM2 organizes nuclear speckles along the cell cycle. As bona-fide splicing factor present in spliceosome structures, SRRM2 deficiency induces skipping of cassette exons with short introns and weak splice sites, tending to change large protein domains. In THP-1 myeloid-like cells, SRRM2 depletion compromises cell viability, upregulates differentiation markers, and sensitizes cells to anti-leukemia drugs. SRRM2 induces a FES splice isoform that attenuates innate inflammatory responses, and MUC1 isoforms that undergo shedding with oncogenic properties. We conclude that SRRM2 acts as a scaffold to organize nuclear speckles, regulating alternative splicing in innate immunity and cell homeostasis.
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Project description:Dysregulation of splicing factor expression plays a crucial role in the progression of hepatocellular carcinoma (HCC). Our research found that the expression level of splicing factor ZMAT2 is increased in HCC, promoting the proliferation of hepatocellular carcinoma cells. RNA-seq data indicated that ZMAT2 regulated exon skipping of mRNA, while RIP-seq data further revealed the binding motifs of ZMAT2. A comprehensive analysis of RNA-seq and RIP-seq data indicateed that ZMAT2 plays a crucial role in the maturation process of TRIM28 mRNA. Deletion of ZMAT2 led to the deletion of 25 bases in exon 11 of TRIM28, ultimately resulting in nonsense-mediated decay (NMD). Previous studies have demonstrated a close association between TRIM28 and the proliferation of hepatocellular carcinoma. Our experiments have revealed that TRIM28 serves as a critical factor for ZMAT2 in facilitating the proliferative process of hepatocellular carcinoma. Studies have demonstrated a close correlation between the mRNA splicing process and the occurrence of phase separation. Our research discovered that ZMAT2 is capable of undergoing phase separation, resulting in the formation of liquid droplet condensates within hepatocellular carcinoma cells. Additionally, it was found that ZMAT2 is able to form protein-nucleic acid condensates with TRIM28 mRNA. In summary, we hypothesize that ZMAT2 and TRIM28 mRNA form protein-nucleic acid condensates, thereby regulating the splicing of TRIM28 mRNA. The augmented expression of ZMAT2 in hepatocellular carcinoma cells results in the upregulation of TRIM28 expression, ultimately driving the proliferation of hepatocellular carcinoma cells.
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Project description:Dysregulation of splicing factor expression plays a crucial role in the progression of hepatocellular carcinoma (HCC). Our research found that the expression level of splicing factor ZMAT2 is increased in HCC, promoting the proliferation of hepatocellular carcinoma cells. RNA-seq data indicated that ZMAT2 regulated exon skipping of mRNA, while RIP-seq data further revealed the binding motifs of ZMAT2. A comprehensive analysis of RNA-seq and RIP-seq data indicateed that ZMAT2 plays a crucial role in the maturation process of TRIM28 mRNA. Deletion of ZMAT2 led to the deletion of 25 bases in exon 11 of TRIM28, ultimately resulting in nonsense-mediated decay (NMD). Previous studies have demonstrated a close association between TRIM28 and the proliferation of hepatocellular carcinoma. Our experiments have revealed that TRIM28 serves as a critical factor for ZMAT2 in facilitating the proliferative process of hepatocellular carcinoma. Studies have demonstrated a close correlation between the mRNA splicing process and the occurrence of phase separation. Our research discovered that ZMAT2 is capable of undergoing phase separation, resulting in the formation of liquid droplet condensates within hepatocellular carcinoma cells. Additionally, it was found that ZMAT2 is able to form protein-nucleic acid condensates with TRIM28 mRNA. In summary, we hypothesize that ZMAT2 and TRIM28 mRNA form protein-nucleic acid condensates, thereby regulating the splicing of TRIM28 mRNA. The augmented expression of ZMAT2 in hepatocellular carcinoma cells results in the upregulation of TRIM28 expression, ultimately driving the proliferation of hepatocellular carcinoma cells.
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