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DNA Methylation Regulates Alternative Polyadenylation via CTCF and the Cohesin Complex

ABSTRACT: Dysregulation of DNA methylation and mRNA alternative cleavage and polyadenylation (APA) are both prevalent in cancer. Through various mechanisms, these processes promote carcinogenesis by altering the production of oncogenes and tumour suppressors. Although promoter DNA methylation is most studied, the majority of differentially methylated regions occur in non-promoter contexts, including the gene 3′ ends, where APA occurs. Using genome-wide methylation sequencing and poly(A)-sequencing we identified a correlation between DNA methylation and APA. As such, we sought to define the mechanism regulating this relationship. Here, we show that DNA methylation regulates APA using CCCTC binding factor (CTCF) binding and recruitment of the cohesin complex. Using data of cancer subtypes available from The Cancer Genome Atlas we authenticated this correlation in vivo. This mechanism of DNA methylation-regulated APA demonstrates the impact of aberrant DNA methylation on transcriptome diversity in cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE131606 | GEO | 2020/03/18

REPOSITORIES: GEO

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DNA Methylation Regulates Alternative Polyadenylation via CTCF and the Cohesin Complex

Project description:Alternative cleavage and polyadenylation (APA) is a form of transcriptional regulation via shifts in how frequently multiple polyadenylation (polyA) sites within genes are used across biological conditions. APA can result in transcripts with varying length and information content, and has been linked to gene regulation in both cancer and development. While trans-acting regulatory factors can cause changes in APA, the process of cleavage and polyadenylation is often co-transcriptional. We hypothesized that epigenetic changes, such as DNA methylation, may regulate APA co-transcriptionally. To identify genes where DNA methylation may regulate APA, we performed a genome-wide quantification of polyA site usage using a next generation sequencing technique. By priming the polyA-tails of an RNA library, we mapped cleavage sites and abundances with base-pair resolution across the genomes of two cell lines. The HCT116 cell line is derived from colon cancer, and contains cancer-associated DNA hypermethylation. The DKO cell line is derived from the parental HCT116 line, but has a near-complete depletion of DNA methylation due to mutations in DNA methyltransferase enzymes. Previous studies have used this sytem to detect genes where promoter DNA methylation regulates the gene expression of tumor suppressors. Analogously, detecting APA between HCT116 and DKO reveals candidate genes where DNA methylation may regulate the process of APA. Mechanistic experiments can further interrogate cross-talk between DNA methylation and APA at these loci, and contribute to the understanding of the function of non-promoter differentially methylated regions.

2020-03-18 | GSE86178 | GEO

hnRNPC regulates cancer-specific alternative cleavage and polyadenylation profiles

Project description:Alternative cleavage and polyadenylation (APA) can occur at more than half of all human genes, greatly enhancing the cellular repertoire of mRNA isoforms. As these isoforms can have altered stability, localisation and coding potential, deregulation of APA can disrupt gene expression and this has been linked to many diseases including cancer progression. How APA generates cancer-specific isoform profiles and what their physiological consequences are, however, is largely unclear. Here we use a subcellular fractionation approach to determine the nuclear and cytoplasmic APA profiles of successive stages of colon cancer using a cell line-based model. Using this approach, we show that during cancer progression specific APA profiles are established. We identify that overexpression of hnRNPC has a critical role in the establishment of APA profiles characteristic for metastatic colon cancer cells, by regulating poly(A) site selection in a subset of genes that have been implicated in cancer progression including MTHFD1L.

2019-06-01 | GSE102357 | GEO

Arginine methylation regulates widespread alternative polyadenylation

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.

2019-01-01 | GSE69904 | GEO

U1 snRNP regulates alternative polyadenylation in DNA damage response

Project description:The DNA damage response (DDR) involves coordinated control of gene expression and DNA repair. Using deep sequencing we found widespread changes of alternative cleavage and polyadenylation (APA) site usage upon UV-treatment in mammalian cells. APA regulation in the 3’ untranslated region (3’UTR) is substantial, leading to both shortening and lengthening of 3’UTRs. Interestingly, a strong activation of intronic APA sites is detected, resulting in widespread expression of truncated transcripts. Intronic APA events are biased to the 5’ end of genes and affect gene groups with important functions in DDR. Moreover, intronic APA site activation during DDR correlates with a decrease in U1 snRNA levels, and this is reversed by U1 snRNA overexpression. Importantly, U1 snRNA overexpression decreases UV-induced apoptosis. Together, these studies describe a significant gene regulatory scheme in DDR where U1 snRNP impacts gene expression via APA.

2016-05-01 | GSE71801 | GEO

Genome-wide profiling reveals cancer-related genes have switched alternative polyadenylation sites in colorectal cancer

Project description:Alternative polyadenylation (APA) is a kind of important post-transcriptional modification in eukaryotic cells. It plays considerable roles in many biological processes and diseases, such as cell differentiation, proliferation and cancer. Here, we used a high-throughput sequencing-based method 3T-seq to investigate the APA pattern in three colorectal cancer patients and explored the biological significance of APA modulation in all the three patients.

2018-02-02 | E-MTAB-6403 | biostudies-arrayexpress

CFIm25 links alternative polyadenylation to glioblastoma tumour suppression

Project description:Purpose: To identify all of the APA targets of CFIm25 on a global scale and develop an algorithm that can idenitify APA events from standard RNA-seq data Methods: RNA from HeLa cells treated with control siRNA and CFIm25 siRNA were subject to RNA-Seq. Using a custom-designed algorithm to mine RNA-seq data for novel APA events regulated by CFIm25. Results: We identified over 1,400 genes with shortened 3’UTRs after CFIm25 knockdown. Importantly, we show that as a consequence of APA, many of these mRNAs have greatly enhanced protein expression due to the loss of destabilizing features within the 3’UTR. Conclusions: Our study underscored the critical function of the CFIm complex members in governing APA and establish a previously unknown link between APA and metabolic pathways important for tumor progression. Hela cell line mRNA profiles of control treated and CFIm25 Knockdown were generated by RNA-Seq using Illumina GAIIx.

2014-05-15 | E-GEOD-42420 | biostudies-arrayexpress

Next generation sequencing to determine alternative cleavage and polyadenylation events among prostate and prostate cancer cell lines

2022-12-29 | GSE86180 | GEO

Analysis of alternative cleavage and polyadenylation by 3' region extraction and deep sequencing

Project description:Alternative cleavage and polyadenylation (APA) generates diverse mRNA isoforms. We developed 3' region extraction and deep sequencing (3'READS) to address mispriming issues that commonly plague poly(A) site (pA) identification, and we used the method to comprehensively map pAs in the mouse genome. Thorough annotation of gene 3' ends revealed over 5,000 previously overlooked pAs (~8% of total) flanked by A-rich sequences, underscoring the necessity of using an accurate tool for pA mapping. About 79% of mRNA genes and 66% of long noncoding RNA genes undergo APA, but these two gene types have distinct usage patterns for pAs in introns and upstream exons. Quantitative analysis of APA isoforms by 3'READS indicated that promoter-distal pAs, regardless of intron or exon locations, become more abundant during embryonic development and cell differentiation and that upregulated isoforms have stronger pAs, suggesting global modulation of the 3' endM-bM-^@M-^Sprocessing activity in development and differentiation. 3'READS to map pAs in mouse genome

2012-12-17 | E-GEOD-42398 | biostudies-arrayexpress

Genetic variants that impact alternative polyadenylation in cancer represent candidate causal risk loci [RNA-seq]

Project description:Alternative polyadenylation (APA) is emerging as a major mechanism of post-transcriptional regulation. APA can impact the development and progression of cancer, suggesting that the genetic determinants of APA might play an important role in regulating cancer risk. Here, we depicted a pan-cancer atlas of human APA quantitative trait loci (apaQTLs), containing approximately 0.7 million apaQTLs across 32 cancer types. Systematic multi-omics analyses indicated that cancer apaQTLs could contribute to APA regulation by altering poly(A) motifs, RNA binding proteins (RBP), and chromatin regulatory elements and were preferentially enriched in GWASidentified cancer susceptibility loci. Moreover, apaQTL-related genes (aGenes) were broadly related to cancer signaling pathways, high mutational burden, immune infiltration, and drug response, implicating their potential as therapeutic targets. Furthermore, apaQTLs were mapped in Chinese colorectal cancer (CRC) tumor tissues and then screened for functional apaQTLs associated with CRC risk in 17,789 cases and 19,951 controls using GWAS-ChIP data, with independent validation in a large-scale population consisting of 6,024 cases and 10,022 controls. A multi-ancestry-associated apaQTL variant rs1020670 with a C>G change in DNM1L was identified, and the G allele contributed to an increased risk of CRC. Mechanistically, the risk variant promoted aberrant APA and facilitated higher usage of DNM1L proximal poly(A) sites mediated by the RBP CSTF2T, which led to higher expression of DNM1L with a short 3'UTR. This stabilized DNM1L to upregulate its expression, provoking CRC cell proliferation. Collectively, these findings generate a resource for understanding APA regulation and the genetic basis of human cancers, providing insights into cancer etiology.

2023-09-29 | GSE241699 | GEO

A comprehensive map of alternative polyadenylation in African American and European American lung cancer patients

Project description:We report the application of a novel method and analysis pipeline that sequences 3’end -enriched RNA to comprehensively map the APA landscape in lung cancer. The goals of this study are to identify the functional role of APA in determining transcriptomic heterogeneity in lung cancer and population differences in APA.

2021-05-13 | GSE174330 | GEO

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