Widespread intronic polyadenylation diversifies immune cell transcriptomes
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA436569 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6795690.fastq.gz | Fastqsanger.gz | |||
| SRR6795700.fastq.gz | Fastqsanger.gz | |||
| SRR6795710.fastq.gz | Fastqsanger.gz | |||
| SRR6795720_1.fastq.gz | Fastqsanger.gz | |||
| SRR6795720_2.fastq.gz | Fastqsanger.gz |
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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:Alternative cleavage and polyadenylation (ApA) is known to alter untranslated region (3'UTR) length but can also recognize intronic polyadenylation (IpA) signals to generate transcripts that lose part or all of the coding region. 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 4927 high-confidence IpA events represented in these cell types. IpA isoforms are widely expressed in immune cells, differentially used during B-cell development or in different cellular environments, and can generate 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. MM cells display a striking loss of IpA isoforms expressed in plasma cells, associated with shorter progression-free survival and impacting key genes in MM biology and response to lenalidomide.
| S-EPMC5928244 | biostudies-literature
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.
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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: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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