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The role of Mediator in small and long noncoding rna production in Arabidopsis thaliana

EMBO JOUrnaL 2011年第5期30卷 814-822页

作者： Kim, Yun Ju Zheng, Binglian Yu, Yu Won, So Youn Mo, Beixin Chen, Xuemei Univ Calif Riverside Dept Bot & Plant Sci Inst Integrat Genome Biol Riverside CA 92521 USA Shenzhen Univ Coll Life Sci Shenzhen Peoples R China

Mediator is a conserved multi-subunit complex known to promote the transcription of protein-coding genes by rna polymerase II (Pol II) in eukaryotes. It has been increasingly realized that Pol II transcribes a large number of intergenic loci to generate noncoding rnas, but the role of Mediator in Pol II-mediated noncoding rna production has been largely unexplored. The role of Mediator in noncoding rna production in plants is particularly intriguing given that plants have evolved from Pol II two additional polymerases, Pol IV and Pol V, to specialize in noncoding rna production and transcriptional gene silencing at heterochromatic loci. Here, we show that Mediator is required for microrna (mirna) biogenesis by recruiting Pol II to promoters of mirna genes. We also show that several well-characterized heterochromatic loci are de-repressed in Mediator mutants and that Mediator promotes Pol II-mediated production of long noncoding scaffold rnas, which serve to recruit Pol V to these loci. This study expands the function of Mediator to include Pol II-mediated intergenic transcription and implicates a role of Mediator in genome stability. The EMBO Journal (2011) 30, 814-822. doi: 10.1038/emboj.2011.3;Published online 21 January 2011

关键词： Mediator microrna noncoding rna Pol II sirna

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The plant Mediator and its role in noncoding rna production

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Frontiers in Biology 2011年第2期6卷 125-132页

作者： Yun Ju KIM Xuemei CHEN Department of Botany and Plant Sciences and Institute of Integrative Genome Biology University of CaliforniaRiversideCA 92521USA

Mediator,a conserved multiprotein complex in animals,plants,and fungi,is a cofactor of rna polymerase II(Pol II).It is known to promote basal Pol II-mediated transcription as well as bridge sequence-specific transcriptional regulators and Pol II to integrate regulatory *** II transcribes not only protein-coding genes but also intergenic regions to generate noncoding rnas such as small rnas(micrornas and small interfering rnas)and long noncoding ***,two plant-specific polymerases,Pol IV and Pol V,have evolved from Pol II and play a role in the production of small interfering rnas and long noncoding rnas at heterochromatic regions to maintain genome stability through transcriptional gene silencing(TGS).Recent studies have defined the composition of the plant Mediator and evaluated its role in noncoding rna production in relationship to Pol II,Pol IV and Pol ***,we review the functions of Mediator and that of noncoding rnas generated by Pol II,Pol IV and Pol V in plants,and discuss a role of Mediator in epigenetic regulation via noncoding rna production.

关键词： small rna noncoding rna Mediator Pol II Pol IV Pol V

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Marked for Life: Epigenetic Effects of Endocrine Disrupting Chemicals

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ANNUAL REVIEW OF ENVIRONMENT AND RESOURCES, VOL 42 2017年 42卷 105-160页

作者： Jacobs, Miriam N. Marczylo, Emma L. Guerrero-Bosagna, Carlos Ruegg, Joelle Publ Hlth England Ctr Radiat Chem & Environm Hazards Chilton OX11 0RQ Oxon England Linkoping Univ Avian Behav Genom & Physiol Grp Dept Phys Chem & Biol SE-58183 Linkoping Sweden Karolinska Inst Unit Toxicol Sci S-15189 Sodertalje Sweden Karolinska Inst Dept Clin Neurosci SE-17177 Stockholm Sweden

The presence of human-made chemical contaminants in the environment has increased rapidly during the past 70 years. Harmful effects of such contaminants were first reported in the late 1950s in wildlife and later in humans. These effects are predominantly induced by endocrine disrupting chemicals (EDCs), chemicals that mimic the actions of endogenous hormones and leave marks at several levels of organization in organisms, from physiological outcomes (phenotypes) to molecular alterations, including epigenetic modifications. Epigenetic mechanisms play pivotal roles in the developmental processes that contribute to determining adult phenotypes, through so-called epigenetic programming. While there is increasing evidence that EDC exposure during sensitive periods of development can perturb epigenetic programming, it is unclear whether these changes are truly predictive of adverse outcomes. Understanding the mechanistic links between EDC-induced epigenetic changes and phenotypic endpoints will be critical for providing improved regulatory tools to better protect the environment and human health from exposure to EDCs.

关键词： endocrine disrupting chemicals DNA methylation histone modification noncoding rna transgenerational epigenetic inheritance chemical risk assessment

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Identifying and annotating human bifunctional rnas reveals their versatile functions

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Science China(Life Sciences) 2016年第10期59卷 981-992页

作者： Geng Chen Juan Yang Jiwei Chen Yunjie Song Ruifang Cao Tieliu Shi Leming Shi Center for Pharmacogenomics School of Pharmacy and School of Life SciencesFudan UniversityShanghai 201203China The Center for Bioinformatics and Computational Biology Shanghai Key Laboratory of Regulatory Biologythe Institute of Biomedical Sciences and School of Life SciencesEast China Normal UniversityShanghai 200241China State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology School of Life SciencesFudan UniversityShanghai 201203China Fudan-Zhangjiang Center for Clinical Genomics Shanghai 201203China Zhanjiang Center for Translational Medicine Shanghai 201203China

Bifunctional rnas that possess both protein-coding and noncoding functional properties were less explored and poorly understood. Here we systematically explored the characteristics and functions of such human bifunctional rnas by integrating tandem mass spectrometry and rna-seq data. We first constructed a pipeline to identify and annotate bifunctional rnas,leading to the characterization of 132 high-confidence bifunctional rnas. Our analyses indicate that bifunctional rnas may be involved in human embryonic development and can be functional in diverse tissues. Moreover, bifunctional rnas could interact with multiple mirnas and rna-binding proteins to exert their corresponding roles. Bifunctional rnas may also function as competing endogenous rnas to regulate the expression of many genes by competing for common targeting mirnas. Finally,somatic mutations of diverse carcinomas may generate harmful effect on corresponding bifunctional rnas. Collectively,our study not only provides the pipeline for identifying and annotating bifunctional rnas but also reveals their important gene-regulatory functions.

关键词： bifunctional rna noncoding rna rna-seq tandem mass spectrometry

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Different phosphoisoforms of rna polymerase II engage the Rtt103 termination factor in a structurally analogous manner

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2017年第20期114卷 E3944-E3953页

作者： Nemec, Corey M. Yang, Fan Gilmore, Joshua M. Hintermair, Corinna Ho, Yi-Hsuan Tseng, Sandra C. Heidemann, Martin Zhang, Ying Florens, Laurence Gasch, Audrey P. Eick, Dirk Washburn, Michael P. Varani, Gabriele Ansari, Aseem Z. Univ Wisconsin Madison Dept Biochem Madison WI 53706 USA Univ Washington Dept Chem Seattle WA 98195 USA Stowers Inst Med Res Kansas City MO 64110 USA Helmholtz Ctr Munich Ctr Integrated Prot Sci Dept Mol Epigenet D-81377 Munich Germany Univ Wisconsin Madison Lab Genet Madison WI 53706 USA Univ Wisconsin Madison Genome Ctr Wisconsin Madison WI 53706 USA Univ Kansas Med Ctr Dept Pathol & Lab Med Kansas City KS 66150 USA Univ Calif San Diego Cell & Dev Biol La Jolla CA 92093 USA

The carboxyl-terminal domain (CTD) of the largest subunit of rna polymerase II (Pol II) orchestrates dynamic recruitment of specific cellular machines during different stages of transcription. Signature phosphorylation patterns of Y1S2P3T4S5P6S7 heptapeptide repeats of the CTD engage specific "readers." Whereas phospho-Ser5 and phospho-Ser2 marks are ubiquitous, phospho-Thr4 is reported to only impact specific genes. Here, we identify a role for phospho-Thr4 in transcription termination at noncoding small nucleolar rna (snorna) genes. Quantitative proteomics reveals an interactome of known readers as well as protein complexes that were not known to rely on Thr4 for association with Pol II. The data indicate a key role for Thr4 in engaging the machinery used for transcription elongation and termination. We focus on Rtt103, a protein that binds phospho-Ser2 and phospho-Thr4 marks and facilitates transcription termination at protein-coding genes. To elucidate how Rtt103 engages two distinct CTD modifications that are differentially enriched at noncoding genes, we relied on NMR analysis of Rtt103 in complex with phospho-Thr4- or phospho-Ser2-bearing CTD peptides. The structural data reveal that Rtt103 interacts with phospho-Thr4 in a manner analogous to its interaction with phospho-Ser2-modified CTD. The same set of hydrogen bonds involving either the oxygen on phospho-Thr4 and the hydroxyl on Ser2, or the phosphate on Ser2 and the Thr4 hydroxyl, can be formed by rotation of an arginine side chain, leaving the intermolecular interface otherwise unperturbed. This economy of design enables Rtt103 to engage Pol II at distinct sets of genes with differentially enriched CTD marks.

关键词： CTD code CTD interactome noncoding rna NMR phosphothreonine

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A functional pseudogene, NMRAL2P, is regulated by Nrf2 and serves as a coactivator of NQO1 in sulforaphane-treated colon cancer cells

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MOLECULAR NUTRITION & FOOD RESEARCH 2017年第4期61卷

作者： Johnson, Gavin S. Li, Jia Beaver, Laura M. Dashwood, W. Mohaiza Sun, Deqiang Rajendran, Praveen Williams, David E. Ho, Emily Dashwood, Roderick H. Texas A&M Hlth Sci Ctr Inst Biosci & Technol Ctr Epigenet & Dis Prevent Houston TX 77030 USA Oregon State Univ Linus Pauling Inst Corvallis OR 97331 USA Oregon State Univ Sch Biol & Populat Hlth Sci Corvallis OR 97331 USA Oregon State Univ Dept Environm & Mol Toxicol Corvallis OR 97331 USA Univ Texas MD Anderson Canc Ctr Dept Clin Canc Prevent Houston TX 77030 USA Texas A&M Univ Dept Nutr & Food Sci College Stn TX 77843 USA Texas A&M Coll Med Dept Mol & Cellular Med College Stn TX 77843 USA

Scope: The anticancer agent sulforaphane (SFN) acts via multiple mechanisms to modulate gene expression, including the induction of nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-dependent signaling and the inhibition of histone deacetylase activity. Transcriptomics studies were performed in SFN-treated human colon cancer cells and in nontransformed colonic epithelial cells in order to pursue new mechanistic leads. Methods and results: rna-sequencing corroborated the expected changes in cancer-related pathways after SFN treatment. In addition to NAD(P)H quinone dehydrogenase 1 (NQO1) and other well-known Nrf2-dependent targets, SFN strongly induced the expression of Loc344887. This noncoding rna was confirmed as a novel functional pseudogene for NmrA-like redox sensor 1, and was given the name NmrA-like redox sensor 2 pseudogene (NMRAL2P). Chromatin immunoprecipitation experiments corroborated the presence of Nrf2 interactions on the NMRAL2P genomic region, and interestingly, NMRAL2P also served as a coregulator of NQO1 in human colon cancer cells. Silencing of NMRAL2P via CRISPR/Cas9 genome-editing protected against SFN-mediated inhibition of cancer cell growth, colony formation, and migration. Conclusion: NMRAL2P is the first functional pseudogene to be identified both as a direct transcriptional target of Nrf2, and as a downstream regulator of Nrf2-dependent NQO1 induction. Further studies are warranted on NMRAL2P-Nrf2 crosstalk and the associated mechanisms of gene regulation.

关键词： Colorectal cancer CRISPR/Cas9 Loc344887 noncoding rna

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Altered expression of MALAT1 lncrna in nonalcoholic steatohepatitis fibrosis regulates CXCL5 in hepatic stellate cells

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TRANSLATIONAL RESEARCH 2017年 190卷 25-39页

作者： Leti, Fatjon Legendre, Christophe Still, Christopher D. Chu, Xin Petrick, Anthony Gerhard, Glenn S. Distefano, Johanna K. Natl Jewish Hlth Denver CO 80206 USA Translat Genom Res Inst Phoenix AZ USA Geisinger Obes Inst Danville PA USA Temple Univ Sch Med Philadelphia PA 19122 USA

In the present study, we sought to identify long noncoding rna (lncrna) expression profiles in nonalcoholic steatohepatitis (NASH) patients with histologic evidence of lobular inflammation and advanced fibrosis. We profiled lncrna expression using rna-sequencing of wedge liver biopsies from 24 nonalcoholic fatty liver disease (NAFLD) patients with normal liver histology, 53 NAFLD patients with lobular inflammation, and 65 NAFLD patients with advanced fibrosis. Transcript profiling identified 4432 and 4057 differentially expressed lncrnas in comparisons of normal tissue with lobular inflammation and fibrosis samples, respectively. Functional enrichment analysis revealed lncrna participation in transforming growth factor beta 1 and tumor necrosis factor signaling, insulin resistance, and extracellular matrix maintenance. Several lncrnas were highly expressed in fibrosis relative to normal tissue, including nuclear paraspeckle assembly transcript 1, hepatocellular carcinoma upregulated lncrna, and metastasis-associated lung adenocarcinoma transcript 1 (MALAT1). Two potential target mrnas, syndecan 4 (SDC4), and C-X-C motif chemokine ligand 5 (CXCL5) were identified for hepatocellular carcinoma upregulated lncrna and MALAT1, respectively, but only CXCL5 showed differential expression among the different histologic classes. Knockdown of MALAT1 expression reduced CXCL5 transcript and protein levels by 50% and 30%, respectively, in HepG2 cells. The expression of MALAT1 and CXCL5 was upregulated in activated hepatic stellate (LX-2) cells compared to cells in the quiescent state, and MALAT1 expression was regulated by hyperglycemia and insulin in HepG2 cells, but only by insulin in LX-2 cells. Dysregulated lncrna expression is associated with inflammation and fibrosis in NASH. Functionally relevant differences in MALAT1 expression may contribute to the development of fibrosis in NASH through mechanisms involving inflammatory chemokines.

关键词： BMIs body mass indexes CXCL5 C-X-C motif chemokine ligand 5 ENA-78 epithelial neutrophil activating peptide 78 HULC hepatocellular carcinoma upregulated lncrna lncrna long noncoding rna MALAT1 metastasis-associated lung adenocarcinoma transcript 1 NAFLD nonalcoholic fatty liver disease NASH nonalcoholic steatohepatitis ncrna noncoding rna NEAT1 nuclear paraspeckle assembly transcript 1 SDC4 syndecan 4 T2D type 2 diabetes TNF tumor necrosis factor TNFA tumor necrosis factor alpha

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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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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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Integrative Analysis Identifies Four Molecular and Clinical Subsets in Uveal Melanoma

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CANCER CELL 2017年第2期32卷 204-+页

作者： Robertson, A. Gordon Shih, Juliann Yau, Christina Gibb, Ewan A. Oba, Junna Mungall, Karen L. Hess, Julian M. Uzunangelov, Vladislav Walter, Vonn Danilova, Ludmila Lichtenberg, Tara M. Kucherlapati, Melanie Kimes, Patrick K. Tang, Ming Penson, Alexander Babur, Ozgun Akbani, Rehan Bristow, Christopher A. Hoadley, Katherine A. Iype, Lisa Chang, Matthew T. Cherniack, Andrew D. Benz, Christopher Mills, Gordon B. Verhaak, Roel G. W. Griewank, Klaus G. Felau, Ina Zenklusen, Jean C. Gershenwald, Jeffrey E. Schoenfield, Lynn Lazar, Alexander J. Abdel-Rahman, Mohamed H. Roman-Roman, Sergio Stern, Marc-Henri Cebulla, Colleen M. Williams, Michelle D. Jager, Martine J. Coupland, Sarah E. Esmaeli, Bita Kandoth, Cyriac Woodman, Scott E. BC Canc Agcy Canadas Michael Smith Genome Sci Ctr Vancouver BC V5Z 4S6 Canada Eli & Edythe L Broad Inst Massachusetts Inst Tech Cambridge MA 02142 USA Dana Farber Canc Inst Dept Med Oncol Boston MA 02215 USA Buck Inst Res Aging Novato CA 94945 USA Univ Texas MD Anderson Canc Ctr Dept Melanoma Med Oncol Houston TX 77030 USA Univ Calif Santa Cruz Ctr Biomol Sci & Engn Dept Biomol Engn Santa Cruz CA 95064 USA Univ North Carolina Chapel Hill Lineberger Comprehens Canc Ctr Chapel Hill NC 27599 USA Penn State Coll Med Dept Publ Hlth Sci 500 Univ Dr Hershey PA 17033 USA Johns Hopkins Univ Sidney Kimmel Comprehens Canc Ctr Baltimore MD 21287 USA Nationwide Childrens Hosp Res Inst Columbus OH 43205 USA Harvard Med Sch Dept Genet Boston MA 02115 USA Brigham & Womens Hosp Div Genet 75 Francis St Boston MA 02115 USA Univ Texas MD Anderson Canc Ctr Dept Genom Med Houston TX 77030 USA Mem Sloan Kettering Canc Ctr Dept Epidemiol & Biostat Human Oncol & Pathogenesis Program New York NY 10021 USA Mem Sloan Kettering Canc Ctr Marie Josee & Henry R Kravis Ctr Mol Oncol 1275 York Ave New York NY 10021 USA Oregon Hlth & Sci Univ Computat Biol Mol & Med Genet Portland OR 97239 USA Univ Texas MD Anderson Canc Ctr Dept Bioinformat & Computat Biol Houston TX 77030 USA Univ Texas MD Anderson Canc Ctr Dept Genom Med Inst Appl Canc Sci Houston TX 77030 USA Univ North Carolina Chapel Hill Dept Genet Chapel Hill NC 27599 USA Inst Syst Biol Seattle WA 98109 USA Univ Calif San Francisco Dept Bioengn San Francisco CA 94122 USA Univ Calif San Francisco Dept Therapeut Sci San Francisco CA 94122 USA Univ Texas MD Anderson Canc Ctr Dept Syst Biol Houston TX 77030 USA Univ Hosp Essen Dept Dermatol D-45157 Essen Germany NCI Ctr Canc Genom Bethesda MD 20892 USA Univ Texas MD Anderson Canc Ctr Dept Surg Oncol Houston TX 77030 USA Ohio State Univ Dept Pathol Wexner Med Ctr Columbus OH 43210 USA Univ Texas MD Anderson Canc Ctr Dept Pathol Dermatol & Translat Mol Pathol

Comprehensive multiplatform analysis of 80 uveal melanomas (UM) identifies four molecularly distinct, clinically relevant subtypes: two associated with poor-prognosis monosomy 3 (M3) and two with better prognosis disomy 3 (D3). We show that BAP1 loss follows M3 occurrence and correlates with a global DNA methylation state that is distinct from D3-UM. Poor-prognosis M3-UM divide into subsets with divergent genomic aberrations, transcriptional features, and clinical outcomes. We report change-of-function SRSF2 mutations. Within D3-UM, ElF1AX- and SRSF2/SF3B/-mutant tumors have distinct somatic copy number alterations and DNA methylation profiles, providing insight into the biology of these low- versus intermediate -risk clinical mutation subtypes.

关键词： EIF1AX GNA11 GNAQ SF3B1 SRSF2 TCGA molecular subtypes monosomy 3 noncoding rna uveal melanoma

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