Pol II phosphorylation regulates a switch between transcriptional and splicing condensates
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA493945 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7943783.fastq.gz | Fastqsanger.gz | |||
| SRR7943784.fastq.gz | Fastqsanger.gz | |||
| SRR7943785.fastq.gz | Fastqsanger.gz | |||
| SRR7943786.fastq.gz | Fastqsanger.gz |
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Project description:The synthesis of pre-mRNA by RNA polymerase II (Pol II) involves the formation of a transcription initiation complex, and a transition to an elongation complex. The large subunit of Pol II contains an intrinsically disordered C-terminal domain that is phosphorylated by cyclin-dependent kinases during the transition from initiation to elongation, thus influencing the interaction of the C-terminal domain with different components of the initiation or the RNA-splicing apparatus. Recent observations suggest that this model provides only a partial picture of the effects of phosphorylation of the C-terminal domain. Both the transcription-initiation machinery and the splicing machinery can form phase-separated condensates that contain large numbers of component molecules: hundreds of molecules of Pol II and mediator are concentrated in condensates at super-enhancers, and large numbers of splicing factors are concentrated in nuclear speckles, some of which occur at highly active transcription sites. Here we investigate whether the phosphorylation of the Pol II C-terminal domain regulates the incorporation of Pol II into phase-separated condensates that are associated with transcription initiation and splicing. We find that the hypophosphorylated C-terminal domain of Pol II is incorporated into mediator condensates and that phosphorylation by regulatory cyclin-dependent kinases reduces this incorporation. We also find that the hyperphosphorylated C-terminal domain is preferentially incorporated into condensates that are formed by splicing factors. These results suggest that phosphorylation of the Pol II C-terminal domain drives an exchange from condensates that are involved in transcription initiation to those that are involved in RNA processing, and implicates phosphorylation as a mechanism that regulates condensate preference.
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Project description:The C-terminal domain of RPB1 (CTD) orchestrates transcription by recruiting regulators to RNA Pol II upon phosphorylation. Recent insights highlight CTD’s pivotal role in driving condensate formation on gene loci. Yet, the molecular mechanism behind how CTD-mediated recruitment of transcriptional regulators influences condensates formation remains unclear. Our study unveils that phosphorylation reversibly dissolves phase separation induced by the unphosphorylated CTD. Phosphorylated CTD, upon specific association with transcription regulatory proteins, forms distinct condensates from unphosphorylated CTD. Function studies demonstrate CTD variants with diverse condensation properties in vitro exhibit difference in promoter binding and mRNA co-processing in cells. Notably, varying CTD lengths lead to alternative splicing outcomes impacting cellular growth, linking the evolution of CTD variation/length with the complexity of splicing from yeast to human. These findings provide compelling evidence for a model wherein post-translational modification enables the transition of functionally specialized condensates, highlighting a co-evolution link between CTD condensation and splicing.
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Project description:The C-terminal domain of RPB1 (CTD) orchestrates transcription by recruiting regulators to RNA Pol II upon phosphorylation. Recent insights highlight CTD’s pivotal role in driving condensate formation on gene loci. Yet, the molecular mechanism behind how CTD-mediated recruitment of transcriptional regulators influences condensates formation remains unclear. Our study unveils that phosphorylation reversibly dissolves phase separation induced by the unphosphorylated CTD. Phosphorylated CTD, upon specific association with transcription regulatory proteins, forms distinct condensates from unphosphorylated CTD. Function studies demonstrate CTD variants with diverse condensation properties in vitro exhibit difference in promoter binding and mRNA co-processing in cells. Notably, varying CTD lengths lead to alternative splicing outcomes impacting cellular growth, linking the evolution of CTD variation/length with the complexity of splicing from yeast to human. These findings provide compelling evidence for a model wherein post-translational modification enables the transition of functionally specialized condensates, highlighting a co-evolution link between CTD condensation and splicing.
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Project description:Hypoxia-induced alternative splicing (AS) controls tumor progression and metastasis. The underlying mechanism specifying hypoxia-responsive AS needs to be determined. We demonstrate the role of nuclear speckle (speckle) nuclear domain (ND) and the long noncoding RNA, MALAT1, in hypoxia-responsive AS. Hypoxia-responsive genes position near speckles, the NDs that enhance splicing efficiency, and their differentially spliced exons harbor features that are characteristic of inefficiently spliced transcripts. Speckle-resident MALAT1, induced in response to hypoxia, boosts hypoxia-responsive AS by regulating the binding of SR-family splicing factor1 (SRSF1) to pre-mRNAs of speckle-associated genes. Mechanistically, MALAT1 facilitates the recruitment of SRSF1 to elongating RNA pol II (RNAP II) by promoting the formation of phase-separated SRSF1 condensates that are preferentially recognized and recruited to pre-mRNA by RNAP II. Our results reveal that MALAT1 boosts hypoxia-induced AS of speckle-associated genes by establishing the threshold concentration of SRSF1 as condensates, thereby promoting RNAP II-mediated recruitment of SRSF1 to pre-mRNAs.
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Project description:Hypoxia-induced alternative splicing (AS) controls tumor progression and metastasis. The underlying mechanism specifying hypoxia-responsive AS needs to be determined. We demonstrate the role of nuclear speckle (speckle) nuclear domain (ND) and the long noncoding RNA, MALAT1, in hypoxia-responsive AS. Hypoxia-responsive genes position near speckles, the NDs that enhance splicing efficiency, and their differentially spliced exons harbor features that are characteristic of inefficiently spliced transcripts. Speckle-resident MALAT1, induced in response to hypoxia, boosts hypoxia-responsive AS by regulating the binding of SR-family splicing factor1 (SRSF1) to pre-mRNAs of speckle-associated genes. Mechanistically, MALAT1 facilitates the recruitment of SRSF1 to elongating RNA pol II (RNAP II) by promoting the formation of phase-separated SRSF1 condensates that are preferentially recognized and recruited to pre-mRNA by RNAP II. Our results reveal that MALAT1 boosts hypoxia-induced AS of speckle-associated genes by establishing the threshold concentration of SRSF1 as condensates, thereby promoting RNAP II-mediated recruitment of SRSF1 to pre-mRNAs.
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