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Regulation by 3′-Untranslated Regions

ANNUAL REVIEW OF GENETICS, VOL 51 2017年第1期51卷 171-194页

作者： Mayr, Christine Mem Sloan Kettering Canc Ctr Dept Canc Biol & Genet New York NY 10065 USA

3'-untranslated regions (3'-UTRs) are the noncoding parts of mrnas. Compared to yeast, in humans, median 3'-UTR length has expanded approximately tenfold alongside an increased generation of alternative 3'-UTR isoforms. In contrast, the number of coding genes, as well as coding region length, has remained similar. This suggests an important role for 3'-UTRs in the biology of higher organisms. 3'-UTRs are best known to regulate diverse fates of mrnas, including degradation, translation, and localization, but they can also function like long noncoding or small rnas, as has been shown for whole 3'-UTRs as well as for cleaved fragments. Furthermore, 3'-UTRs determine the fate of proteins through the regulation of protein-protein interactions. They facilitate cotranslational protein complex formation, which establishes a role for 3'-UTRs as evolved eukaryotic operons. Whereas bacterial operons promote the interaction of two subunits, 3'-UTRs enable the formation of protein complexes with diverse compositions. All of these 3'-UTR functions are accomplished by effector proteins that are recruited by rna-binding proteins that bind to 3'-UTR cis-elements. In summary, 3'-UTRs seem to be major players in gene regulation that enable local functions, compartmentalization, and cooperativity, which makes them important tools for the regulation of phenotypic diversity of higher organisms.

关键词： noncoding rna regulatory rna alternative 3 '-UTRs alternative polyadenylation cotranslational protein complex formation cellular organization mrna localization rna-binding proteins cooperativity accessibility of regulatory elements

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Biological Activities of Extracellular Vesicles and Their Cargos from Bovine and Human Milk in Humans and Implications for Infants

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JOUrnaL OF NUTRITION 2017年第1期147卷 3-10页

作者： Zempleni, Janos Aguilar-Lozano, Ana Sadri, Mahrou Sukreet, Sonal Manca, Sonia Wu, Di Zhou, Fang Mutai, Ezra Univ Nebraska Lincoln Dept Nutr & Hlth Sci Lincoln NE 68588 USA

Extracellular vesicles (EVs) in milk harbor a variety of compounds, including lipids, proteins, noncoding rnas, and mrnas. Among the various classes of EVs, exosomes are of particular interest, because cargo sorting in exosomes is a regulated, nonrandom process and exosomes play essential roles in cell-to-cell communication. Encapsulation in exosomes confers protection against enzymatic and nonenzymatic degradation of cargos and provides a pathway for cellular uptake of cargos by endocytosis of exosomes. Compelling evidence suggests that exosomes in bovine milk are transported by intestinal cells, vascular endothelial cells, and macrophages in human and rodent cell cultures, and bovine-milk exosomes are delivered to peripheral tissues in mice. Evidence also suggests that cargos in bovine-milk exosomes, in particular rnas, are delivered to circulating immune cells in humans. Some micrornas and mrnas in bovine-milk exosomes may regulate the expression of human genes and be translated into protein, respectively. Some exosome cargos are quantitatively minor in the diet compared with endogenous synthesis. However, noncanonical pathways have been identified through which low concentrations of dietary micrornas may alter gene expression, such as the accumulation of exosomes in the immune cell microenvironment and the binding of micrornas to Toll-like receptors. Phenotypes observed in infant feeding studies include higher Mental Developmental Index, Psychomotor Development Index, and Preschool Language Scale-3 scores in breastfed infants than in those fed various formulas. In mice, supplementation with plant-derived MIR-2911 improved the antiviral response compared with controls. Porcine-milk exosomes promote the proliferation of intestinal cells in mice. This article discusses the above-mentioned advances in research concerning milk exosomes and their cargos in human nutrition. Implications for infant nutrition are emphasized, where permitted, but data in infants are limit

关键词： biological activity bovine milk human milk microrna noncoding rna exosomes extracellular vesicles infants

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The Roles of noncoding rnas in the Carcinogenesis and Development of Cutaneous Squamous Cell Carcinoma

The Roles of Noncoding RNAs in the Carcinogenesis and Develo...

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第十五次中国暨国际生物物理大会

作者： Liang Zhou Yinghui Wang Lin Gao Pengfei Wang Shanshan Li Zhenhua Ding Department of Radiation Medicine Guangdong Provincial Key Laboratory of Tropical Disease Research School of Public HealthSouthern Medical University

Cutaneous squamous cell carcinoma(CSCC) is the second most common cancer with an annual incidence of over one million *** sun exposure can damage the DNA of normal keratinocytes in the epidermis, primarily via ultraviolet(UV) radiation, and lead to the development of skin cancer including ***, the underlying molecular mechanism(s) responsible for this transition remain to be fully *** rnas, including micro rnas(mirnas) and long noncoding rnas(Lnc rnas), do not encode protein and are active players in diverse physiological and pathological ***, highly-conserved single chain noncoding rnas with 19～25 nt in length, negatively regulate gene expression at the posttranscriptional *** expression of mirnas supports the initiation and progression of diseases, including *** R-365 is one of the highest expressed mirnas induced by UV exposure.A series studies from our group have discovered miR-365 as a major oncomi R contributing CSCC carcinogenesis and *** downstream target genes of miR-365, including NFIB, BAX and HOXA9, manipulate critical cellular processes, like cell cycle, apoptosis and glycolysis, to promote CSCC carcinogenesis and *** roles of Lnc rnas in CSCC remain poorly ***, our group found that MALAT1 is critical for epidermal growth factor receptor(EGFR) protein expression in CSCC, which is mediated by kinectin 1(KTN1).MALAT1 physically interacts with c-MYC to enhance KTN1 *** finding of c-MYCassisted MALAT1-KTN1-EGFR axis is conserved in several types of cancers, suggesting a promising target axis for therapeutic intervention of CSCC.

关键词： noncoding rna mirna Long noncoding rna miR-365 HOXA9 MALAT1

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Discovering lncrna mediated sponge interactions in breast cancer molecular subtypes

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BMC GENOMICS 2018年第1期19卷 650-650页

作者： Olgun, Gulden Sahin, Ozgur Tastan, Oznur Bilkent Univ Dept Comp Engn TR-06800 Ankara Turkey Bilkent Univ Fac Sci Dept Mol Biol & Genet TR-06800 Ankara Turkey Sabanci Univ Fac Engn & Nat Sci TR-34956 Istanbul Turkey

Background: Long non-coding rnas (lncrnas) can indirectly regulate mrnas expression levels by sequestering micrornas (mirnas), and act as competing endogenous rnas (cernas) or as sponges. Previous studies identified lncrna-mediated sponge interactions in various cancers including the breast cancer. However, breast cancer subtypes are quite distinct in terms of their molecular profiles;therefore, cernas are expected to be subtype-specific as well. Results: To find lncrna-mediated cerna interactions in breast cancer subtypes, we develop an integrative approach. We conduct partial correlation analysis and kernel independence tests on patient gene expression profiles and further refine the candidate interactions with mirna target information. We find that although there are sponges common to multiple subtypes, there are also distinct subtype-specific interactions. Functional enrichment of mrnas that participate in these interactions highlights distinct biological processes for different subtypes. Interestingly, some of the cernas also reside in close proximity in the genome;for example, those involving HOX genes, HOTAIR, miR-196a-1 and miR-196a-2. We also discover subtype-specific sponge interactions with high prognostic potential. We found that patients differ significantly in their survival distributions if they are group based on the expression patterns of specific cerna interactions. However, it is not the case if the expression of individual rnas participating in cerna is used. Conclusion: These results can help shed light on subtype-specific mechanisms of breast cancer, and the methodology developed herein can help uncover sponges in other diseases.

关键词： lncrna mediated sponges cerna interactions noncoding rna mirna lncrna Partial correlation analysis Kernel conditional independence test

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Perturbed maintenance of transcriptional repression on the inactive X-chromosome in the mouse brain after Xist deletion

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EPIGENETICS & CHROMATIN 2018年第1期11卷 50-50页

作者： Adrianse, Robin L. Smith, Kaleb Gatbonton-Schwager, Tonibelle Sripathy, Smitha P. Lao, Uyen Foss, Eric J. Boers, Ruben G. Boers, Joachim B. Gribnau, Joost Bedalov, Antonio Fred Hutchinson Canc Res Ctr Clin Res Div 1100 Fairview Ave N Seattle WA 98109 USA Univ Washington Dept Biochem Seattle WA 98195 USA Univ Washington Dept Med Seattle WA 98195 USA Erasmus MC Dept Dev Biol NL-3015 CN Rotterdam Netherlands Erasmus MC Dept Obstet & Gynaecol NL-3015 CN Rotterdam Netherlands Delft Diagnost Labs NL-2288 ER Rijswijk Netherlands

Background: The long noncoding rna Xist is critical for initiation and establishment of X-chromosome inactivation during embryogenesis in mammals, but it is unclear whether its continued expression is required for maintaining X-inactivation in vivo. Results: By using an inactive X-chromosome-linked MeCP2-GFP reporter, which allowed us to enumerate reactivation events in the mouse brain even when they occur in very few cells, we found that deletion of Xist in the brain after establishment of X-chromosome inactivation leads to reactivation in 2-5% of neurons and in a smaller fraction of astrocytes. In contrast to global loss of both H3 lysine 27 trimethylation (H3K27m3) and histone H2A lysine 119 monoubiquitylation (H2AK119ub1) we observed upon Xist deletion, alterations in CpG methylation were subtle, and this was mirrored by only minor alterations in X-chromosome-wide gene expression levels, with highly expressed genes more prone to both derepression and demethylation compared to genes with low expression level. Conclusion: Our results demonstrate that Xist plays a role in the maintenance of histone repressive marks, DNA methylation and transcriptional repression on the inactive X-chromosome, but that partial loss of X-dosage compensation in the absence of Xist in the brain is well tolerated.

关键词： X-chromosome inactivation Xist noncoding rna MeCP2 Rett syndrome

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Alternative 3′-end processing of long noncoding rna initiates construction of nuclear paraspeckles

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EMBO JOUrnaL 2012年第20期31卷 4020-4034页

作者： Naganuma, Takao Nakagawa, Shinichi Tanigawa, Akie Sasaki, Yasnory F. Goshima, Naoki Hirose, Tetsuro Natl Inst Adv Ind Sci & Technol Biomed Informat Res Ctr Funct RNom Team Tokyo 1350064 Japan RIKEN Adv Sci Inst RNA Biol Lab Wako Saitama Japan Natl Inst Adv Ind Sci & Technol Biomed Informat Res Ctr Biol Syst Control Team Tokyo 1350064 Japan

Paraspeckles are unique subnuclear structures built around a specific long noncoding rna, NEAT1, which is comprised of two isoforms produced by alternative 3'-end processing (NEAT1_1 and NEAT1_2). To address the precise molecular processes that lead to paraspeckle formation, we identified 35 paraspeckle proteins (PSPs), mainly by colocalization screening with a fluorescent protein-tagged full-length cDNA library. Most of the newly identified PSPs possessed various putative rna-binding domains. Subsequent rnai analyses identified seven essential PSPs for paraspeckle formation. One of the essential PSPs, HNRNPK, appeared to affect the production of the essential NEAT1_2 isoform by negatively regulating the 3'-end polyadenylation of the NEAT1_1 isoform. An in vitro 3'-end processing assay revealed that HNRNPK arrested binding of the CPSF6-NUDT21 (CFIm) complex in the vicinity of the alternative polyadenylation site of NEAT1_1. In vitro binding assays showed that HNRNPK competed with CPSF6 for binding to NUDT21, which was the underlying mechanism to arrest CFIm binding by HNRNPK. This HNRNPK function led to the preferential accumulation of NEAT1_2 and initiated paraspeckle construction with multiple PSPs. The EMBO Journal (2012) 31, 4020-4034. doi:10.1038/emboj.2012.251;Published online 7 September 2012

关键词： alternative rna processing noncoding rna nuclear body rna-binding proteins

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. Yeast rna-Binding Protein Nab3 Regulates Genes Involved in Nitrogen Metabolism

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MOLECULAR AND CELLULAR BIOLOGY 2017年第18期37卷 e00154-17-e00154-17页

作者： Merran, Jonathan Corden, Jeffry L. Johns Hopkins Univ Sch Med Dept Mol Biol & Genet Baltimore MD 21218 USA

Termination of Saccharomyces cerevisiae rna polymerase II (Pol II) transcripts occurs through two alternative pathways. Termination of mrnas is coupled to cleavage and polyadenylation while noncoding transcripts are terminated through the Nrd1-Nab3-Sen1 (NNS) pathway in a process that is linked to rna degradation by the nuclear exosome. Some mrna transcripts are also attenuated through premature termination directed by the NNS complex. In this paper we present the results of nuclear depletion of the NNS component Nab3. As expected, many noncoding rnas fail to terminate properly. In addition, we observe that nitrogen catabolite-repressed genes are upregulated by Nab3 depletion.

关键词： nitrogen metabolism noncoding rna termination transcription

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Role of post-transcriptional regulation of mrna stability in renal pathophysiology: focus on chronic kidney disease

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FASEB JOUrnaL 2017年第2期31卷 457-468页

作者： Feigerlova, Eva Battaglia-Hsu, Shyue-Fang CHU Poitiers Serv Endocrinol Pole DUNE Poitiers France Univ Poitiers Unite Format & Rech Med Pharm Poitiers France INSERM Clin Invest Ctr 1402 Unite 1082 Poitiers France Univ Lorraine INSERM Unite 954 Nutr Genet & Exposit Risques Environm Vandoeuvre Les Nancy France Ctr Hosp Reg Univ Nancy Vandoeuvre Ies Nancy France

Chronic kidney disease (CKD) represents an important public health problem. Its progression to end-stage renal disease is associated with increased morbidity and mortality. The determinants of renal function decline are not fully understood. Recent progress in the understanding of post-transcriptional regulation of mrna stability has helped the identification of both the trans-and cis-acting elements of mrna as potential markers and therapeutic targets for difficult-to-diagnose and -treat diseases, including CKDs such as diabetic nephropathy. Human antigen R (HuR), a trans-acting element of mrna, is an rna binding factor (RBF) best known for its ability to stabilize AU-rich-element-containing mrnas. Deregulated HuR subcellular localization or expression occurs in a wide range of renal diseases, such as metabolic acidosis, ischemia, and fibrosis. Besides RBFs, recent evidence revealed that noncoding rna, such as microrna and long noncoding rna, participates in regulating mrna stability and that aberrant noncoding rna expression accounts for many pathologic renal conditions. The goal of this review is to provide an overview of our current understanding of the post-transcriptional regulation of mrna stability in renal pathophysiology and to offer perspectives for this class of diseases. We use examples of diverse renal diseases to illustrate different mrna stability pathways in specific cellular compartments and discuss the roles and impacts of both the cis- and trans-activating factors on the regulation of mrna stability in these diseases.-Feigerlova a, E., Battaglia-Hsu, S.-F. Role of post-transcriptional regulation of mrna stability in renal pathophysiology: focus on chronic kidney disease.

关键词： rna binding factor noncoding rna P-body stress granule rna-exosome

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Ser7 of rnaPII-CTD facilitates heterochromatin formation by linking ncrna to rnai

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2017年第52期114卷 E11208-E11217页

作者： Kajitani, Takuya Kato, Hiroaki Chikashige, Yuji Tsutsumi, Chihiro Hiraoka, Yasushi Kimura, Hiroshi Ohkawa, Yasuyuki Obuse, Chikashi Hermand, Damien Murakami, Yota Hokkaido Univ Grad Sch Sci Sapporo Hokkaido 0600810 Japan Kyoto Univ Grad Sch Med Kyoto 6068507 Japan Shimane Univ Sch Med Dept Biochem Izumo Shimane 6938501 Japan Natl Inst Informat & Commun Technol Adv ICT Res Inst Frontier Res Lab Kobe Hyogo 6512492 Japan Osaka Univ Grad Sch Frontier Biosci Suita Osaka 5650871 Japan Tokyo Inst Technol Grad Sch Biosci & Biotechnol Yokohama Kanagawa 2268501 Japan Kyushu Univ Japan Sci & Technol Agcy Core Res Evolut Sci & Technol Div TranscriptMed Inst Bioregulat Fukuoka 8128582 Japan Osaka Univ Grad Sch Sci Toyonaka Osaka 5600043 Japan Univ Namur Namur Res Coll B-5000 Namur Belgium

Some long noncoding rnas (ncrnas) transcribed by rna polymerase II (rnaPII) are retained on chromatin, where they regulate rnai and chromatin structure. The molecular basis of this retention remains unknown. We show that in fission yeast serine 7 (Ser7) of the C-terminal domain (CTD) of rnaPII is required for efficient sirna generation for rnai-dependent heterochromatin formation. Surprisingly, Ser7 facilitates chromatin retention of nascent heterochromatic rnas (hrnas). Chromatin retention of hrnas and sirna generation requires both Ser7 and an rna-binding activity of the chromodomain of Chp1, a subunit of the rna-induced transcriptional silencing (RITS) complex. Furthermore, RITS associates with rnaPII in a Ser7-dependent manner. We propose that Ser7 promotes cotranscriptional chromatin retention of hrna by recruiting the rna-chromatin connector protein Chp1, which facilitates rnai-dependent hetero-chromatin formation. Our findings reveal a function of the CTD code: linking ncrna transcription to rnai for heterochromatin formation.

关键词： heterochromatin rnai noncoding rna rna polymerase II

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Insights into the Establishment of Chromatin States in Pluripotent Cells from Studies of X Inactivation

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JOUrnaL OF MOLECULAR BIOLOGY 2017年第10期429卷 1521-1531页

作者： Postlmayr, Andreas Wutz, Anton Swiss Fed Inst Technol Zurich Inst Mol Hlth Sci Otto Stern Weg 7 CH-8093 Zurich Switzerland Univ Zurich Life Sci Zurich Grad Sch Mol Life Sci Program CH-8049 Zurich Switzerland

Animal development entails the sequential and coordinated specialization of cells. During cell differentiation, transcription factors, cell signaling pathways, and chromatin-associated protein complexes cooperate in regulating the expression of a large number of genes. Here, we review the present understanding of the establishment of chromatin states by focusing on X chromosome inactivation (XCI) as a model for facultative heterochromatin formation in female embryonic cells. The inactive X chromosome is large enough to be investigated by biochemical and microscopy techniques. In addition, the ability to compare the inactivated chromatin to the active X in male cells enables us to differentiate events specific to gene silencing during XCI from gene regulatory effects from changing pathways in the same cell. Findings in XCI are useful as blueprints for investigation of the action of epigenetic pathways in differentiation and lineage commitment. We summarize recent studies that have identified factors that are critical for chromosome-wide gene repression in XCI, and we discuss their implications for epigenetic regulation in pluripotent cells of the early embryo. (C) 2017 Elsevier Ltd. All rights reserved.

关键词： animal development pluripotent stem cell chromatin noncoding rna gene regulation

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