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Cristina Hoehener, Iris Hug, Mariusz Nowacki
Dicer proteins are known to produce small RNAs (sRNAs) from long double-stranded RNA (dsRNA) templates. These sRNAs are bound by Argonaute proteins, which select the guide strand, often with a 5' end sequence bias. However, Dicer proteins have never been shown to have sequence cleavage preferences. In Paramecium development, two classes of sRNAs that are required for DNA elimination are produced by three Dicer-like enzymes: Dcl2, Dcl3, and Dcl5. Through in vitro cleavage assays, we demonstrate that Dcl2 has a strict size preference for 25 nt and a sequence preference for 5' U and 5' AGA, while Dcl3 has a sequence preference for 5' UNG...
March 1, 2018: Cell
Do-Hwan Lim, Seungjae Lee, Jee Yun Han, Min-Seok Choi, Jae-Sang Hong, Youngmo Seong, Young-Soo Kwon, Young Sik Lee
The steroid hormone ecdysone has a central role in the developmental transitions of insects through its control of responsive protein-coding and microRNA (miRNA) gene expression. However, the complete regulatory network controlling the expression of these genes remains to be elucidated. In this study, we performed cross-linking immunoprecipitation coupled with deep sequencing of endogenous Argonaute 1 (Ago1) protein, the core effector of the miRNA pathway, in Drosophila S2 cells. We found that regulatory interactions between miRNAs and their cognate targets were substantially altered by Ago1 in response to ecdysone signaling...
March 15, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Tong Sun, Shin-Yi Du, Joshua Armenia, Fangfang Qu, Jingyu Fan, Xiaodong Wang, Teng Fei, Kazumasa Komura, Shirley X Liu, Gwo-Shu Mary Lee, Philip W Kantoff
Mechanisms by which non-coding RNAs contribute to the progression of hormone-sensitive prostate cancer (PCa) (HSPC) to castration-resistant PCa (CRPC) remain largely unknown. We previously showed that microRNA-221/222 is up-regulated in CRPC and plays a critical role in modulating androgen receptor function during CRPC development. With further investigation, we characterized a putative promoter region located 23.3 kb upstream of the miR-221/222 gene, and this promoter is differentially activated in CRPC LNCaP-Abl cells, leading to the up-regulation of miR-221/222...
March 13, 2018: Oncogenesis
Aaron Balasingam Koenig, Juan Martín Barajas, María Jose Guerrero, Kalpana Ghoshal
MicroRNAs are ~22 nucleotide RNAs that regulate gene expression at the post-transcriptional level by binding messenger RNA transcripts. miR-21 is described as an oncomiR whose steady-state levels are commonly increased in many malignancies, including hepatocellular carcinoma (HCC). Methods known as cross-linking and immunoprecipitation of RNA followed by sequencing (CLIP-seq) have enabled transcriptome-wide identification of miRNA interactomes. In our study, we use a publicly available Argonaute-CLIP dataset (GSE97061), which contains nine HCC cases with matched benign livers, to characterize the miR-21 interactome in HCC...
March 14, 2018: International Journal of Molecular Sciences
Audrone Lapinaite, Jennifer A Doudna, Jamie H D Cate
Argonaute proteins (Agos) are present in all domains of life. Although the physiological function of eukaryotic Agos in regulating gene expression is well documented, the biological roles of many of their prokaryotic counterparts remain enigmatic. In some bacteria, Agos are associated with CRISPR (clustered regularly interspaced short palindromic repeats) loci and use noncanonical 5'-hydroxylated guide RNAs (gRNAs) for nucleic acid targeting. Here we show that using 5-bromo-2'-deoxyuridine (BrdU) as the 5' nucleotide of gRNAs stabilizes in vitro reconstituted CRISPR-associated Marinitoga piezophila Argonaute-gRNA complexes (MpAgo RNPs) and significantly improves their specificity and affinity for RNA targets...
March 12, 2018: Proceedings of the National Academy of Sciences of the United States of America
Daniel M Dayeh, Bradley C Kruithoff, Kotaro Nakanishi
Some gene transcripts have cellular functions as regulatory noncoding RNAs. For example, ~23 nucleotide (nt)-long small interfering RNAs (siRNAs) are loaded into Argonaute proteins. The resultant ribonucleoprotein assembly, the RNA-induced silencing complex (RISC), cleaves RNAs that are extensively base-paired with the loaded siRNA. To date, base complementarity is recognized as the major determinant of specific target cleavage (or slicing), but little is known about how Argonaute inspects base pairing before cleavage...
March 8, 2018: Journal of Biological Chemistry
Susie Choi, Hironori Uehara, Yuanyuan Wu, Subrata Das, Xiaohui Zhang, Bonnie Archer, Lara Carroll, Balamurali Krishna Ambati
Short-activating RNA (saRNA), which targets gene promoters, has been shown to increase the target gene expression. In this study, we describe the use of an saRNA (Flt a-1) to target the flt-1 promoter, leading to upregulation of the soluble isoform of Flt-1 and inhibition of angiogenesis. We demonstrate that Flt a-1 increased sFlt-1 mRNA and protein levels, while reducing VEGF expression. This was associated with suppression of human umbilical vascular endothelial cell (HUVEC) proliferation and cell cycle arrest at the G0/G1 phase...
2018: PloS One
Yasuhiro Mie, Yu Hirano, Keiko Kowata, Akiyoshi Nakamura, Mayu Yasunaga, Yoshihiro Nakajima, Yasuo Komatsu
MicroRNA (miRNA)-guided argonaute (Ago) controls gene expression upon binding to the 3' UTR of mRNA. The miRNA function can be competitively inhibited by single-stranded anti-miRNA oligonucleotides (AMOs). In this study, we constructed a novel type of AMO flanked by interstrand cross-linked 2'-O-methylated RNA duplexes (CLs) that confer a stable helical conformation. Compared with other structured AMOs, AMO flanked by CLs at the 5' and 3' termini exhibited much higher inhibitory activity in cells. Anti-miRNA activity, nuclease resistance, and miRNA modification pattern distinctly differed according to the CL-connected positions in AMOs...
March 2, 2018: Molecular Therapy. Nucleic Acids
P M Clark, N Chitnis, M Shieh, M Kamoun, F B Johnson, D Monos
The MHC is recognized for its importance in human health and disease. However, many disease-associated variants throughout the region remain of unknown significance, residing predominantly within non-coding regions of the MHC. The characterization of non-coding RNA transcripts throughout the MHC is thus central to understanding the genetic contribution of these variants. Therefore, we characterize novel miRNA transcripts throughout the MHC by performing deep RNA sequencing of two B lymphoblastoid cell lines with completely characterized MHC haplotypes...
March 1, 2018: Scientific Reports
Haiyang Hu, Jian-Mei Liu, Zhenyu Hu, Xi Jiang, Xiaode Yang, Jiangxia Li, Yao Zhang, Haijing Yu, Philipp Khaitovich
MicroRNA (miRNA) sponges are vital components of posttranscriptional gene regulation. Yet, only a limited number of miRNA sponges have been identified. Here, we show that the recently evolved non-coding tumor suppressor transcript, antisense RNA to TP73 gene (TP73-AS1), functions as a natural sponge of human-specific miRNA miR-941. We find unusually nine high-affinity miR-941 binding sites clustering within 1kb region on TP73-AS1, which forms miR-941 sponge region. This sponge region displays increased sequence constraint only in humans, and its formation can be traced to the tandem expansion of a 71-nt-long sequence containing a single miR-941 binding site in old world monkeys...
February 20, 2018: Molecular Biology and Evolution
Xiaobai Liu, Jian Zheng, Yixue Xue, Hai Yu, Wei Gong, Ping Wang, Zhen Li, Yunhui Liu
Rationale: PIWI-interacting RNAs (piRNAs), a class of newly discovered small RNA molecules that function by binding to the Argonaute protein family (i.e., the PIWIL protein subfamily), and long noncoding RNAs (lncRNA) are implicated in several cancers. However, the detailed roles of ncRNAs in glioma remain unclear. Methods: The expression of PIWIL3, piR-30188, OIP5-AS1, miR-367, CEBPA and TRAF4 were measured in glioma tissues and cells. The role of PIWIL3/OIP5-AS1/miR-367-3p/CEBPA feedback loop was evaluated in cell and animal models...
2018: Theranostics
Wen Tang, Meetu Seth, Shikui Tu, En-Zhi Shen, Qian Li, Masaki Shirayama, Zhiping Weng, Craig C Mello
In metazoans, Piwi-related Argonaute proteins engage piRNAs (Piwi-interacting small RNAs) to defend the genome against invasive nucleic acids, such as transposable elements. Yet many organisms-including worms and humans-express thousands of piRNAs that do not target transposons, suggesting that piRNA function extends beyond genome defense. Here, we show that the X chromosome-derived piRNA 21ux-1 downregulates XOL-1 (XO Lethal), a master regulator of X chromosome dosage compensation and sex determination in Caenorhabditis elegans...
February 13, 2018: Developmental Cell
Meetu Seth, Masaki Shirayama, Wen Tang, En-Zhi Shen, Shikui Tu, Heng-Chi Lee, Zhiping Weng, Craig C Mello
Protein-coding genes undergo a wide array of regulatory interactions with factors that engage non-coding regions. Open reading frames (ORFs), in contrast, are thought to be constrained by coding function, precluding a major role in gene regulation. Here, we explore Piwi-interacting (pi)RNA-mediated transgene silencing in C. elegans and show that marked differences in the sensitivity to piRNA silencing map to the endogenous sequences within transgene ORFs. Artificially increasing piRNA targeting within the ORF of a resistant transgene can lead to a partial yet stable reduction in expression, revealing that piRNAs not only silence but can also "tune" gene expression...
February 14, 2018: Cell Reports
En-Zhi Shen, Hao Chen, Ahmet R Ozturk, Shikui Tu, Masaki Shirayama, Wen Tang, Yue-He Ding, Si-Yuan Dai, Zhiping Weng, Craig C Mello
piRNAs (Piwi-interacting small RNAs) engage Piwi Argonautes to silence transposons and promote fertility in animal germlines. Genetic and computational studies have suggested that C. elegans piRNAs tolerate mismatched pairing and in principle could target every transcript. Here we employ in vivo cross-linking to identify transcriptome-wide interactions between piRNAs and target RNAs. We show that piRNAs engage all germline mRNAs and that piRNA binding follows microRNA-like pairing rules. Targeting correlates better with binding energy than with piRNA abundance, suggesting that piRNA concentration does not limit targeting...
February 10, 2018: Cell
Quyet Nguyen, Akihide Iritani, Shuhei Ohkita, Ba V Vu, Kana Yokoya, Ai Matsubara, Ken-Ichi Ikeda, Nobuhiro Suzuki, Hitoshi Nakayashiki
No abstract text is available yet for this article.
February 14, 2018: Nucleic Acids Research
Hanna Iribe, Kengo Miyamoto, Tomoko Takahashi, Yoshiaki Kobayashi, Jastina Leo, Misako Aida, Kumiko Ui-Tei
Chemical modifications of 2'-O-methyl (2'-OMe) and locked nucleic acid (LNA) of the nucleotides in the seed region (positions 2-8) of the small interfering RNA (siRNA) guide strand significantly reduced seed-matched (SM) off-target effects. The siRNA with 2'-OMe modifications inhibited the expression of a completely-matched (CM) target gene, whereas that with LNA modifications did not inhibit the expression of the CM target. By computational predictions of conformational changes of siRNA by these modifications, we revealed that both modifications in the siRNA seed region reduce SM off-target effects by steric hindrance to base-pairing with target transcripts but LNA modifications also disturb the association of the siRNA guide strand with the Argonaute (AGO) protein by altering RNA conformation...
May 31, 2017: ACS Omega
Maria C Ow, Kirill Borziak, Alexandra M Nichitean, Steve Dorus, Sarah E Hall
Environmental stress during early development in animals can have profound effects on adult phenotypes via programmed changes in gene expression. Using the nematode C. elegans, we demonstrated previously that adults retain a cellular memory of their developmental experience that is manifested by differences in gene expression and life history traits; however, the sophistication of this system in response to different environmental stresses, and how it dictates phenotypic plasticity in adults that contribute to increased fitness in response to distinct environmental challenges, was unknown...
February 15, 2018: PLoS Genetics
Saife Niaz
Small RNAs govern almost every biological process in eukaryotes associating with the Argonaute proteins to form the RNA-induced silencing complex (mRISC). Argonaute proteins constitute the core of RISCs with different members having variety of protein binding partners and biochemical properties. This review focuses on the AGO subfamily of the Argonautes that are ubiquitously expressed and are associated with small RNAs. The structure, function and the role of the AGO proteins in the cell is discussed in detail...
November 27, 2017: Biological Chemistry
Mei-Yan Qi, Jing-Wen Song, Zhuo Zhang, Shuang Huang, Qing Jing
Tristetraprolin (TTP) destabilizes AU-rich element (ARE)-containing mRNA by directly binding with their 3'UTR. P38 stimulation substantially increases ARE-mRNA stability, at least through repressing TTP. However, the mechanism by which P38 keeps TTP inactive has not been fully understood. TTP and ARE-mRNA localize to processing bodies (PBs), the mRNA granules associated with mRNA silencing. Here, we detected the influence of P38 upon TTP localization within PBs and found that P38 regulates TTP localization within PBs...
February 14, 2018: Molecular Biology of the Cell
Jiahe Li, Connie Wu, Wade Wang, Yanpu He, Elad Elkayam, Leemor Joshua-Tor, Paula T Hammond
Small interfering RNA (siRNA) represents a promising class of inhibitors in both fundamental research and the clinic. Numerous delivery vehicles have been developed to facilitate siRNA delivery. Nevertheless, achieving highly potent RNA interference (RNAi) toward clinical translation requires efficient formation of RNA-induced gene-silencing complex (RISC) in the cytoplasm. Here we coencapsulate siRNA and the central RNAi effector protein Argonaute 2 (Ago2) via different delivery carriers as a platform to augment RNAi...
February 5, 2018: Proceedings of the National Academy of Sciences of the United States of America
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