| 1. |
- Boele, Joost, et al.
(författare)
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PAPD5-mediated 3' adenylation and subsequent degradation of miR-21 is disrupted in proliferative disease.
- 2014
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Ingår i: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 111:31, s. 11467-11472
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Tidskriftsartikel (refereegranskat)abstract
- Next-generation sequencing experiments have shown that microRNAs (miRNAs) are expressed in many different isoforms (isomiRs), whose biological relevance is often unclear. We found that mature miR-21, the most widely researched miRNA because of its importance in human disease, is produced in two prevalent isomiR forms that differ by 1 nt at their 3' end, and moreover that the 3' end of miR-21 is posttranscriptionally adenylated by the noncanonical poly(A) polymerase PAPD5. PAPD5 knockdown caused an increase in the miR-21 expression level, suggesting that PAPD5-mediated adenylation of miR-21 leads to its degradation. Exoribonuclease knockdown experiments followed by small-RNA sequencing suggested that PARN degrades miR-21 in the 3'-to-5' direction. In accordance with this model, microarray expression profiling demonstrated that PAPD5 knockdown results in a down-regulation of miR-21 target mRNAs. We found that disruption of the miR-21 adenylation and degradation pathway is a general feature in tumors across a wide range of tissues, as evidenced by data from The Cancer Genome Atlas, as well as in the noncancerous proliferative disease psoriasis. We conclude that PAPD5 and PARN mediate degradation of oncogenic miRNA miR-21 through a tailing and trimming process, and that this pathway is disrupted in cancer and other proliferative diseases.
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| 2. |
- Horie, Masafumi, et al.
(författare)
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Integrative CAGE and DNA Methylation Profiling Identify Epigenetically Regulated Genes in NSCLC
- 2017
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Ingår i: Molecular Cancer Research. - : AMER ASSOC CANCER RESEARCH. - 1541-7786 .- 1557-3125. ; 15:10, s. 1354-1365
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Tidskriftsartikel (refereegranskat)abstract
- Lung cancer is the leading cause of cancer-related deaths worldwide. The majority of cancer driver mutations have been identified; however, relevant epigenetic regulation involved in tumorigenesis has only been fragmentarily analyzed. Epigenetically regulated genes have a great theranostic potential, especially in tumors with no apparent driver mutations. Here, epigenetically regulated genes were identified in lung cancer by an integrative analysis of promoter-level expression profiles from Cap Analysis of Gene Expression (CAGE) of 16 nonsmall cell lung cancer (NSCLC) cell lines and 16 normal lung primary cell specimens with DNA methylation data of 69 NSCLC cell lines and 6 normal lung epithelial cells. A core set of 49 coding genes and 10 long noncoding RNAs (lncRNA), which are upregulated in NSCLC cell lines due to promoter hypomethylation, was uncovered. Twenty-two epigenetically regulated genes were validated (upregulated genes with hypomethylated promoters) in the adenocarcinoma and squamous cell cancer subtypes of lung cancer using The Cancer Genome Atlas data. Furthermore, it was demonstrated that multiple copies of the REP522 DNA repeat family are prominently upregulated due to hypomethylation in NSCLC cell lines, which leads to cancer-specific expression of lncRNAs, such as RP1-90G24.10, AL022344.4, and PCAT7. Finally, Myeloma Overexpressed (MYEOV) was identified as the most promising candidate. Functional studies demonstrated that MYEOV promotes cell proliferation, survival, and invasion. Moreover, high MYEOV expression levels were associated with poor prognosis. (C) 2017 AACR.
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| 3. |
- Horie, Masafumi, et al.
(författare)
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Transcriptome analysis of periodontitis-associated fibroblasts by CAGE sequencing identified DLX5 and RUNX2 long variant as novel regulators involved in periodontitis
- 2016
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- Periodontitis is affecting over half of the adult population, and represents a major public health problem. Previously, we isolated a subset of gingival fibroblasts (GFs) from periodontitis patients, designated as periodontitis-associated fibroblasts (PAFs), which were highly capable of collagen degradation. To elucidate their molecular profiles, GFs isolated form healthy and periodontitis-affected gingival tissues were analyzed by CAGE-seq and integrated with the FANTOM5 atlas. GFs from healthy gingival tissues displayed distinctive patterns of CAGE profiles as compared to fibroblasts from other organ sites and characterized by specific expression of developmentally important transcription factors such as BARX1, PAX9, LHX8, and DLX5. In addition, a novel long non-coding RNA associated with LHX8 was described. Furthermore, we identified DLX5 regulating expression of the long variant of RUNX2 transcript, which was specifically active in GFs but not in their periodontitis-affected counterparts. Knockdown of these factors in GFs resulted in altered expression of extracellular matrix (ECM) components. These results indicate activation of DLX5 and RUNX2 via its distal promoter represents a unique feature of GFs, and is important for ECM regulation. Down-regulation of these transcription factors in PAFs could be associated with their property to degrade collagen, which may impact on the process of periodontitis.
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