Effect of INTS11, INTS9, CPSF73 knockdown on transcription
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA854600 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR19908300.fastq.gz | Fastqsanger.gz | |||
| SRR19908301.fastq.gz | Fastqsanger.gz | |||
| SRR19908302.fastq.gz | Fastqsanger.gz | |||
| SRR19908303.fastq.gz | Fastqsanger.gz | |||
| SRR19908304.fastq.gz | Fastqsanger.gz |
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Project description:As a key component for transcription, Transcriptional results of INTS11 knockdown were analyzed by chromatin associated RNA sequencing (ChrRNA-seq). We used ChrRNA-seq, 4sU-seq and TT-seq data of HCT116-INTS11-AID cells under normal condition, induction condition and recovery condition, and HCT116-INTS9-AID cells, Chrna-seq data of HCT116-CPSF73-AID cells before and after protein knockdown were analyzed for gene expression profile.
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Project description:As Integrator is tightly associated with RNAPII-CTD, it is critical to understand how the RNAPII engaged and conducted within the active gene promoter for divergent transcription. We thus employed RNAPII ChIP-seq (Chromatin Immuno-precipitation with RNAPII antibody) to determine the distribution of the total RNAPII and its phosphorylation isoforms. Total RNA polymerase II and its carbon terminal phosphorylation(RNA polymerase II-ctd-Tyr-1，RNA polymerase II-ctd-ser-2) before and after INTS11 knockdown in HCT116-INTS11-AID cells changes chromatin immunoprecipitation DNA sequencing (ChIP-seq).
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Project description:Termination is a ubiquitous phase in every transcription cycle but is incompletely understood and a subject of debate. We have used gene editing as a new approach to address its mechanism through engineered conditional depletion of the 5’-3’ exonuclease, Xrn2, or the polyadenylation signal (PAS) endonuclease, CPSF73. The ability to rapidly control Xrn2 reveals a clear and general role for it in co-transcriptional degradation of 3’ flanking region RNA and transcriptional termination. This defect is characterised genome-wide, at high resolution, using native elongating transcript sequencing (mNET-seq). An Xrn2 effect on termination requires prior RNA cleavage and we provide evidence for this by showing that catalytically inactive CPSF73 cannot restore termination to cells lacking functional CPSF73. Notably, Xrn2 plays no significant role in either Histone or snRNA gene termination even though both RNA classes undergo 3’ end cleavage. In sum, efficient termination on most protein-coding genes involves CPSF73 mediated RNA cleavage and co-transcriptional degradation of polymerase-associated RNA by Xrn2. However, as CPSF73 loss caused more extensive read-through transcription than Xrn2 elimination, it likely plays a more underpinning role in termination.
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Project description:RNA polymerase II (RNAPII) transcription initiates bidirectionally at many human protein-coding genes. Sense transcription usually dominates and leads to messenger RNA production, whereas antisense transcription rapidly terminates. The basis for this directionality is not fully understood. Here, we show that sense transcriptional initiation is more efficient and focused than in the antisense direction. After transcription begins, directionality is maintained by the opposing functions of Integrator (INTS11) and cyclin-dependent kinase 9 (CDK9). INTS11 terminates antisense transcription, whereas sense transcription is protected from this attenuation by CDK9. However, INTS11 terminates transcription in both directions upon CDK9 inhibition, and the engineered recruitment of CDK9 abrogates attenuation by INTS11. Therefore, transcriptional initiation and the asymmetric activities of CDK9 and INTS11 explain the attenuation of antisense transcription, the more extensive nature of sense transcription, and promoter directionality.
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Project description:Multiple types of cellular stress induce RNA polymerase II (Pol II) to read through normal termination sites at mRNA genes, causing long downstream regions to be transcribed. We observed strong read-through transcription downstream of thousands of genes after heat shock. Additionally, the 3’ Pol II pause that normally occurs during termination was globally lost. Heat shock also increased phosphorylation of Tyr1 and Ser2 residues in the Pol II C-terminal domain (CTD) at the 3’ ends of genes, with smaller increases observed at genes with read-through transcription. We found that 3’ RNA cleavage, a key step of transcription termination, was defective at read-through genes after heat shock; however, the CPSF73 endonuclease responsible for cleavage remained at the 3’ ends of genes. Over-expressing an activator of CPSF73 activity, RBBP6, during heat shock rescued the loss of cleavage and attenuated read-through transcription. Our data suggest that heat shock alters Pol II speed, CTD phosphorylation, and CPSF73 activity via RBBP6, contributing to a multifaceted mechanism that enables transcription to continue far downstream of normal termination sites during cellular stress.
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Project description:Multiple types of cellular stress induce RNA polymerase II (Pol II) to read through normal termination sites at mRNA genes, causing long downstream regions to be transcribed. We observed strong read-through transcription downstream of thousands of genes after heat shock. Additionally, the 3’ Pol II pause that normally occurs during termination was globally lost. Heat shock also increased phosphorylation of Tyr1 and Ser2 residues in the Pol II C-terminal domain (CTD) at the 3’ ends of genes, with smaller increases observed at genes with read-through transcription. We found that 3’ RNA cleavage, a key step of transcription termination, was defective at read-through genes after heat shock; however, the CPSF73 endonuclease responsible for cleavage remained at the 3’ ends of genes. Over-expressing an activator of CPSF73 activity, RBBP6, during heat shock rescued the loss of cleavage and attenuated read-through transcription. Our data suggest that heat shock alters Pol II speed, CTD phosphorylation, and CPSF73 activity via RBBP6, contributing to a multifaceted mechanism that enables transcription to continue far downstream of normal termination sites during cellular stress.
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Project description:Cleavage by the endonuclease CPSF73 and polyadenylation of nascent RNA is an essential step in co-transcriptional mRNA maturation, and abnormal poly(A) site choices have been associated with human diseases, including cancer. Recent work has surprisingly identified CPSF73 as a promising drug target for inhibiting the growth of specific cancers. However, our understanding of the regulation of CPSF73 is still at an early stage. Here, we report that a HECT-like E3 ligase, UBE3D, participates in stabilizing CPFS73 protein by preventing its ubiquitin-mediated degradation by the proteasome. Depletion of UBE3D in both non-cancer cells and cancer cells leads to CPSF73 downregulation, a pre-mRNA cleavage defect and dysregulated gene expression. UBE3D dysfunction or chemical inactivation of CPFS73 inhibited migration and invasion as well as stem cell renewal phenotypes in vitro in triple negative breast cancer cells. Our findings indicate that targeting the pre-mRNA processing nuclease CPSF73 has potential for breast cancer therapy.
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Project description:Cleavage by the endonuclease CPSF73 and polyadenylation of nascent RNA is an essential step in co-transcriptional mRNA maturation, and abnormal poly(A) site choices have been associated with human diseases, including cancer. Recent work has surprisingly identified CPSF73 as a promising drug target for inhibiting the growth of specific cancers. However, our understanding of the regulation of CPSF73 is still at an early stage. Here, we report that a HECT-like E3 ligase, UBE3D, participates in stabilizing CPFS73 protein by preventing its ubiquitin-mediated degradation by the proteasome. Depletion of UBE3D in both non-cancer cells and cancer cells leads to CPSF73 downregulation, a pre-mRNA cleavage defect and dysregulated gene expression. UBE3D dysfunction or chemical inactivation of CPFS73 inhibited migration and invasion as well as stem cell renewal phenotypes in vitro in triple negative breast cancer cells. Our findings indicate that targeting the pre-mRNA processing nuclease CPSF73 has potential for breast cancer therapy.
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Project description:RNA polymerase II (RNAPII) transcription initiates bidirectionally at many human protein-coding genes. Sense transcription usually dominates and leads to messenger RNA production, whereas antisense transcription rapidly terminates. The basis for this directionality is not fully understood. Here, we show that sense transcriptional initiation is more efficient and focused than in the antisense direction. After transcription begins, directionality is maintained by the opposing functions of Integrator (INTS11) and cyclin-dependent kinase 9 (CDK9). INTS11 terminates antisense transcription, whereas sense transcription is protected from this attenuation by CDK9. However, INTS11 terminates transcription in both directions upon CDK9 inhibition, and the engineered recruitment of CDK9 abrogates attenuation by INTS11. Therefore, transcriptional initiation and the asymmetric activities of CDK9 and INTS11 explain the attenuation of antisense transcription, the more extensive nature of sense transcription, and promoter directionality.
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Project description:RNA polymerase II (RNAPII) transcription initiates bidirectionally at many human protein-coding genes. Sense transcription usually dominates and leads to messenger RNA production, whereas antisense transcription rapidly terminates. The basis for this directionality is not fully understood. Here, we show that sense transcriptional initiation is more efficient and focused than in the antisense direction. After transcription begins, directionality is maintained by the opposing functions of Integrator (INTS11) and cyclin-dependent kinase 9 (CDK9). INTS11 terminates antisense transcription, whereas sense transcription is protected from this attenuation by CDK9. However, INTS11 terminates transcription in both directions upon CDK9 inhibition, and the engineered recruitment of CDK9 abrogates attenuation by INTS11. Therefore, transcriptional initiation and the asymmetric activities of CDK9 and INTS11 explain the attenuation of antisense transcription, the more extensive nature of sense transcription, and promoter directionality.
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