Widespread intronic polyadenylation inactivates tumor suppressor genes in leukemia
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA438149 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6830250.fastq.gz | Fastqsanger.gz | |||
| SRR6830260.fastq.gz | Fastqsanger.gz | |||
| SRR6830270_1.fastq.gz | Fastqsanger.gz | |||
| SRR6830270_2.fastq.gz | Fastqsanger.gz | |||
| SRR6830251.fastq.gz | Fastqsanger.gz |
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Project description:DNA mutations are known cancer drivers. Here, we investigated if mRNA events that are upregulated in cancer can functionally mimic the outcome of genetic alterations. 3′-seq or RNA-seq were applied to normal and malignant B cells from chronic lymphocytic leukemia (CLL; N = 59). We discovered widespread upregulation of truncated mRNAs and proteins in primary CLL cells that were not generated by genetic alterations but occurred through intronic polyadenylation (IPA). IPA-generated truncated mRNAs were often recurrent (N = 330) and predominantly affected genes with tumor-suppressive functions. The IPA-generated truncated proteins often lack the tumor-suppressive functions of the corresponding full-length proteins (DICER, FOXN3), and several even acted in an oncogenic manner (CARD11, MGA, CHST11). In CLL, inactivation of tumor-suppressor genes (TSGs) through aberrant mRNA processing is substantially more prevalent than loss of TSGs through genetic events. We further identified novel TSG candidates that are inactivated by IPA in leukemia and by truncating DNA mutations in solid tumors. These genes are understudied in cancer as their overall mutation rates are lower than those of well-known TSGs. Our findings show the need to go beyond genomic analyses in cancer diagnostics, as mRNA events that are silent at the DNA level are widespread contributors to cancer pathogenesis through inactivation of TSGs.
2018-06-25 | GSE111793 | GEO
Project description:Widespread intronic polyadenylation diversifies immune cell transcriptomes
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Project description:DNA mutations are known cancer drivers. Here we investigated whether mRNA events that are upregulated in cancer can functionally mimic the outcome of genetic alterations. RNA sequencing or 3'-end sequencing techniques were applied to normal and malignant B cells from 59 patients with chronic lymphocytic leukaemia (CLL)1-3. We discovered widespread upregulation of truncated mRNAs and proteins in primary CLL cells that were not generated by genetic alterations but instead occurred by intronic polyadenylation. Truncated mRNAs caused by intronic polyadenylation were recurrent (n = 330) and predominantly affected genes with tumour-suppressive functions. The truncated proteins generated by intronic polyadenylation often lack the tumour-suppressive functions of the corresponding full-length proteins (such as DICER and FOXN3), and several even acted in an oncogenic manner (such as CARD11, MGA and CHST11). In CLL, the inactivation of tumour-suppressor genes by aberrant mRNA processing is substantially more prevalent than the functional loss of such genes through genetic events. We further identified new candidate tumour-suppressor genes that are inactivated by intronic polyadenylation in leukaemia and by truncating DNA mutations in solid tumours4,5. These genes are understudied in cancer, as their overall mutation rates are lower than those of well-known tumour-suppressor genes. Our findings show the need to go beyond genomic analyses in cancer diagnostics, as mRNA events that are silent at the DNA level are widespread contributors to cancer pathogenesis through the inactivation of tumour-suppressor genes.
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Project description:Alternative cleavage and polyadenylation (ApA) can generate mRNA isoforms with differences in 3'UTR length without changing the coding region (CDR). However, ApA can also recognize intronic polyadenylation (IpA) signals to generate transcripts that lose part or all of the CDR. We analyzed 46 3'-seq and RNA-seq profiles from normal human tissues, primary immune cells, and multiple myeloma (MM) samples and created an atlas of 4,927 high confidence IpA events represented in these cell types. Up to 16% of expressed genes in immune cells generate IpA isoforms, a majority of which are differentially used during B cell development or in different cellular environments, while MM cells display a striking loss of IpA isoforms expressed in plasma cells (PCs), their cell type of origin. IpA events can lead to truncated proteins lacking C-terminal functional domains. This can mimic ectodomain shedding through loss of transmembrane domains or alter the binding specificity of proteins with DNA-binding or protein-protein interaction domains, thus contributing to diversification of the transcriptome. In MM, loss of expression of PC IpA isoforms is associated with shorter progression-free survival and impacts key genes in MM biology and response to the therapeutic lenalidomide, including those encoding the transcription factor IKZF1 and core E3 ubiquitin ligase complex component CUL4A.
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Project description:We explored the regulation of intronic polyadenylation (IPA) isoforms by doxorubicin and HuR in several subcellular compartments.
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Project description:Mutations that attenuate DNA repair by homologous recombination (HR) promote tumorigenesis and sensitize cells to chemotherapeutic agents that cause replication fork collapse, a phenotype known as “BRCAness.” BRCAness tumors arise from loss-of-function mutations in 22 genes. Of these genes, all but one (Cdk12) directly function in the HR repair pathway. Cdk12 phosphorylates Serine 2 of the RNA Polymerase II (RNAPII) C-terminal domain (CTD) heptapeptide repeat, a modification that regulates transcription elongation, splicing, and cleavage/polyadenylation. Genome-wide expression studies suggest that Cdk12 depletion abrogates the expression of several HR genes relatively specifically, blunting HR repair. This observation suggests that Cdk12 mutational status may predict tumor sensitivity to targeted treatments against BRCAness, such as Parp 1 inhibitors, and that small-molecule inhibitors of Cdk12 may induce sensitization of otherwise HR-competent tumors to these treatments. Despite this growing clinical interest, the mechanism behind the apparent specificity of Cdk12 in regulating HR genes remains unknown. Here we find that Cdk12 globally suppresses intronic polyadenylation events, enabling the production of full-length gene products. Many HR genes harbor significantly more intronic polyadenylation sites compared to all expressed genes, and the cumulative effect of these sites accounts for the increased sensitivity of HR gene expression to Cdk12 loss. Finally, we find evidence that Cdk12 loss-of-function mutations cause increased intronic polyadenylation within HR genes in human tumors, suggesting that this mechanism is conserved. This work clarifies the biological function of CDK12 and underscores its potential both as a chemotherapeutic target and as a tumor biomarker.
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Project description:We explored the regulation of intronic polyadenylation (IPA) isoforms by doxorubicin and HuR in breast cancer cells.
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Project description:We investigated the regulation by doxorubicin of HuR binding to RNA near intronic polyadenylation (IPA) sites in several subcellular compartments of breast cancer cells.
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Project description:Alternative polyadenylation (APA) has recently been recognized as a universal mechanism for gene regulation, but it remains unclear how APA is controlled. Here we report that the Arabidopsis thaliana Protein Arginine Methyltransferase 10 (AtPRMT10) regulates global APA with its protein partner HLP1, a conserved hnRNP A/B protein. HLP1 binds preferentially to A-rich and U-rich cis-elements around polyadenylation sites, thereby linking AtPRMT10 to the control of APA through protein-protein interactions. AtPRMT10 mutations cause significant proximal-to-distal poly(A) site shifts largely overlapping with those in hlp1-1 mutants. Proximal polyadenylation is maintained by AtPRMT10-directed methylation and is mediated in part by methylation of HLP1 at specific arginine residues. Our findings demonstrate that arginine methylation of an RNA-binding protein adds a novel layer of regulation to widespread alternative polyadenylation.
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Project description:Synaptic activity induces well-known changes in enhancer-promoter driven gene expression but also induces changes in splicing and polyadenylation that are understudied. Here, we investigate the mechanism of expression for alternative polyadenylation isoform Homer1a, an immediate early gene essential to synaptic plasticity. We report that neuronal activation, in neuronal cultures and in adult mouse brain, depletes the splice factor U1 snRNP from Homer1 pre-mRNA and that this causes shifted utilization of a cryptic polyadenylation signal within intron 5 resulting in Homer1a expression. Because U1 snRNP is a ubiquitous splice factor, we tested the generality of activity-driven U1 snRNP depletion as a mechanism for gene expression using RNA immunoprecipitation sequencing. Analysis reveals that neuronal activity changes U1 snRNP binding to ~2000 transcripts and for a subset of transcripts, a reduction in U1 snRNP binding was accompanied by utilization of a cryptic intronic polyadenylation site. This subset is enriched for transcripts encoding synaptic proteins involved in excitability control. Genes demonstrating activity-dependent reduced U1 snRNP binding often encode a binding motif for Sam68, a neuronal alternative polyadenylation factor. Findings reveal that activity-driven changes in intron utilization for transcript termination serves an important role in synaptic plasticity.
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