Integrative Regulatory Mapping Indicates that the RNA-Binding Protein HuR Couples Pre-mRNA Processing and mRNA Stability

Mukherjee, Neelanjan; Corcoran, David L.; Nusbaum, Jeffrey D.; Reid, David W.; Georgiev, Stoyan; Hafner, Markus; Ascano, Manuel; Tuschl, Thomas; Ohler, Uwe; Keene, Jack D.

doi:10.1016/j.molcel.2011.06.007

Cited by 601 publications

(775 citation statements)

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“…The agreement between the methods is significant (p < 1.91 £ 10 ¡10 , Fisher's exact test), and higher than observed in previous comparisons. 27 RIP-Seq targets that were absent in the iCLIP data tend to be transcripts with low expression levels (data not shown), confirming our expectation that RIP-Seq is the more abundance-sensitive method with higher coverage than iCLIP. Besides interactions with mRNAs and pre-mRNAs, we identified 2 miRNAs as putative hnRNP H1 targets (miR-612 and miR-3652), and 12 long non-coding RNAs (NEAT1, SNHG3, MALAT1, FTX, SNHG4, TUG1, HOTAIRM1, GNAS-AS1, MIR22HG, BDNF-AS, OIP5-AS1, MIR17HG).…”

Section: Identification Of Target Transcripts and Binding Sitessupporting

confidence: 77%

High-throughput analyses of hnRNP H1 dissects its multi-functional aspect

et al. 2016

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ABSTRACThnRNPs are polyvalent RNA binding proteins that have been implicated in a range of regulatory roles including splicing, mRNA decay, translation, and miRNA metabolism. A variety of genome wide studies have taken advantage of methods like CLIP and RIP to identify the targets and binding sites of RNA binding proteins. However, due to the complex nature of RNA-binding proteins, these studies are incomplete without assays that characterize the impact of RBP binding on mRNA target expression. Here we used a suite of high-throughput approaches (RIP-Seq, iCLIP, RNA-Seq and shotgun proteomics) to provide a comprehensive view of hnRNP H1s ensemble of targets and its role in splicing, mRNA decay, and translation. The combination of RIP-Seq and iCLIP allowed us to identify a set of 1,086 high confidence target transcripts. Binding site motif analysis of these targets suggests the TGGG tetramer as a prevalent component of hnRNP H1 binding motif, with particular enrichment around intronic hnRNP H1 sites. Our analysis of the target transcripts and binding sites indicates that hnRNP H1s involvement in splicing is 2-fold: it directly affects a substantial number of splicing events, but also regulates the expression of major components of the splicing machinery and other RBPs with known roles in splicing regulation. The identified mRNA targets displayed function enrichment in MAPK signaling and ubiquitin mediated proteolysis, which might be main routes by which hnRNP H1 promotes tumorigenesis.

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Section: Identification Of Target Transcripts and Binding Sitessupporting

confidence: 77%

High-throughput analyses of hnRNP H1 dissects its multi-functional aspect

et al. 2016

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“…The regulation of cytokines by miR-9 is HuR-dependent HuR is a known regulator of inflammation by mediating the stability and the translation of mRNAs holding ARE motifs, 16 moreover, all the cytokines in this study deregulated by miR-9 contain several repeats of the HuR-binding motif identified recently by PAR-CLIP 25,26 (Supplementary 3B). Because we found HuR to be a direct target of miR-9, we next analysed the role of HuR in the regulation of cytokines by miR-9.…”

Section: Introductionmentioning

confidence: 60%

Inhibition of miR-9 de-represses HuR and DICER1 and impairs Hodgkin lymphoma tumour outgrowth in vivo

et al. 2012

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MicroRNAs are important regulators of gene expression in normal development and disease. miR-9 is overexpressed in several cancer forms, including brain tumours, hepatocellular carcinomas, breast cancer and Hodgkin lymphoma (HL). Here we demonstrated a relevance for miR-9 in HL pathogenesis and identified two new targets Dicer1 and HuR. HL is characterized by a massive infiltration of immune cells and fibroblasts in the tumour, whereas malignant cells represent only 1% of the tumour mass. These infiltrates provide important survival and growth signals to the tumour cells, and several lines of evidence indicate that they are essential for the persistence of HL. We show that inhibition of miR-9 leads to derepression of DICER and HuR, which in turn results in a decrease in cytokine production by HL cells followed by an impaired ability to attract normal inflammatory cells. Finally, inhibition of miR-9 by a systemically delivered antimiR-9 in a xenograft model of HL increases the protein levels of HuR and DICER1 and results in decreased tumour outgrowth, confirming that miR-9 actively participates in HL pathogenesis and points to miR-9 as a potential therapeutic target.Oncogene ( Keywords: miR-9; cytokines; Hodgkin lymphoma; HuR; DICER1 INTRODUCTIONChronic inflammation is a well-recognized cause of cancer and up to 25% of all cancers are thought to be induced by either chronic infections or autoimmune diseases. 1 Inflammation not only works as a tumour-promoting agent but also influences other steps of tumorigenesis by inducing DNA damage, angiogenesis, invasion and metastasis. 2 Hodgkin lymphoma (HL) is one of the most frequent lymphomas in the western world 3 and it can be divided in several subtypes based on the morphology, composition of the infiltrates and the phenotype of the immune cells. The nodular sclerosis subtype is the most common subtype of classical HL (cHL) and accounts for about 60--70% of the cHL cases, followed by mixed cellularity cHL accounting for 20--25%.cHL is an unusual B-cell malignancy in which the tumour cells represent only 1% of the tumour bulk, whereas the vast majority of the cells are a mixture of infiltrating immune cells and fibroblasts actively attracted via chemokine secretion by the malignant cells, the so-called Hodgkin and Reed --Sternberg cells. 3 Several lines of evidence indicate that the infiltrating cells are necessary for the survival of the HL cells by providing growth and survival signals, and protection from NK cells. 3,4 MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression at the posttranscriptional level by base-pairing to target mRNAs and promoting transcript instability and/or translational repression. 5 Mature miRNAs derive from long hairpin precursors that are sequentially processed by the RNase-III-type enzymes DROSHA and DICER1, respectively. 5 miRNAs have been implicated in several physiological and pathological events and can act as both tumour suppressors and oncogenes. 6

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“…Our results show that methylated RNAs tend to be more abundant than nonmethylated RNAs (Figure 3a–e) in old vs. young. In addition, CDF analysis of AUF1 and HuR target mRNAs (Mukherjee et al., 2011; Yoon et al., 2014) from MeRIP‐seq and total RNA‐seq data has shown that AUF1 and HuR target RNAs are downregulated further than nontarget mRNAs once they are methylated (Figure 3f,g, Figures S2 and S3). These results imply possible involvement of AUF1 and HuR in the stability regulation of m6A‐modified RNA (Visvanathan et al., 2017).…”

Section: Resultsmentioning

confidence: 99%

Profiling of m6A RNA modifications identified an age‐associated regulation of AGO2 mRNA stability

et al. 2018

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SummaryGene expression is dynamically regulated in a variety of mammalian physiologies. During mammalian aging, there are changes that occur in protein expression that are highly controlled by the regulatory steps in transcription, post‐transcription, and post‐translation. Although there are global profiles of human transcripts during the aging processes available, the mechanism(s) by which transcripts are differentially expressed between young and old cohorts remains unclear. Here, we report on N6‐methyladenosine (m6A) RNA modification profiles of human peripheral blood mononuclear cells (PBMCs) from young and old cohorts. An m6A RNA profile identified a decrease in overall RNA methylation during the aging process as well as the predominant modification on proteincoding mRNAs. The m6A‐modified transcripts tend to be more highly expressed than nonmodified ones. Among the many methylated mRNAs, those of DROSHA and AGO2 were heavily methylated in young PBMCs which coincided with a decreased steady‐state level of AGO2 mRNA in the old PBMC cohort. Similarly, downregulation of AGO2 in proliferating human diploid fibroblasts (HDFs) also correlated with a decrease in AGO2 mRNA modifications and steady‐state levels. In addition, the overexpression of RNA methyltransferases stabilized AGO2 mRNA but not DROSHA and DICER1 mRNA in HDFs. Moreover, the abundance of miRNAs also changed in the young and old PBMCs which are possibly due to a correlation with AGO2 expression as observed in AGO2‐depleted HDFs. Taken together, we uncovered the role of mRNA methylation on the abundance of AGO2 mRNA resulting in the repression of miRNA expression during the process of human aging.

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Integrative Regulatory Mapping Indicates that the RNA-Binding Protein HuR Couples Pre-mRNA Processing and mRNA Stability

Cited by 601 publications

References 51 publications

High-throughput analyses of hnRNP H1 dissects its multi-functional aspect

High-throughput analyses of hnRNP H1 dissects its multi-functional aspect

Inhibition of miR-9 de-represses HuR and DICER1 and impairs Hodgkin lymphoma tumour outgrowth in vivo

Profiling of m6A RNA modifications identified an age‐associated regulation of AGO2 mRNA stability

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