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Epigenetic modulations of noncoding rna: a novel dimension of Cancer biology

MOLECULAR CANCER 2020年第1期19卷 64-64页

作者： Yang, Xiao Liu, Ming Li, Mengmeng Zhang, Sen Hiju, Hong Sun, Jing Mao, Zhihai Zheng, Minhua Feng, Bo Shanghai Jiao Tong Univ Sch Med Ruijin Hosp Dept Gen SurgDiv Gastrointestinal & Colorectal S Shanghai 200205 Peoples R China Shanghai Jiao Tong Univ Sch Med Tongren Hosp Dept Genecol & Obstet Shanghai 200205 Peoples R China Tongji Univ Sch Med Shanghai Peoples Hosp 10 Shanghai 200205 Peoples R China

Empowered by recent advances of sequencing techniques, transcriptome-wide studies have characterized over 150 different types of post-transcriptional chemical modifications of rna, ranging from methylations of single base to complex installing reactions catalyzed by coordinated actions of multiple modification enzymes. These modifications have been shown to regulate the function and fate of rnas and further affecting various cellular events. However, the current understanding of their biological functions in human diseases, especially in cancers, is still limited. Once regarded as "junk" or "noise" of the transcriptome, noncoding rna (ncrna) has been proved to be involved in a plethora of cellular signaling pathways especially those regulating cancer initiation and progression. Accumulating evidence has demonstrated that ncrnas manipulate multiple phenotypes of cancer cells including proliferation, metastasis and chemoresistance and may become promising biomarkers and targets for diagnosis and treatment of cancer. Importantly, recent studies have mapped plenty of modified residues in ncrna transcripts, indicating the existence of epigenetic modulation of ncrnas and the potential effects of rna modulation on cancer progression. In this review, we briefly introduced the characteristics of several main epigenetic marks on ncrnas and summarized their consecutive effects on cancer cells. We found that ncrnas could act both as regulators and targets of epigenetic enzymes, which indicated a cross-regulating network in cancer cells and unveil a novel dimension of cancer biology. Moreover, by epitomizing the knowledge of rna epigenetics, our work may pave the way for the design of patient-tailored therapeutics of cancers.

关键词： rna epigenetics noncoding rna Cancer progression Cancer treatment

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Photoperiod-and thermo-sensitive genic male sterility in rice are caused by a point mutation in a novel noncoding rna that produces a small rna

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细胞研究（英文版） 2012年第4期22卷 649-660页

作者： Hai Zhou Qinjian Liu Jing Li Dagang Jiang Lingyan Zhou Ping Wu Sen Lu Feng Li Liya Zhu Zhenlan Liu Letian Chen Yao-Guang Liu Chuxiong Zhuang State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources College of Life Sciences South China Agricultural University Guangzhou Guangdong 510642 China Zhongkai University of Agriculture and Engineering Guangzhou Guangdong 510225 China

Photoperiod- and thermo-sensitive genic male sterility (PGMS and TGMS) are the core components for hybrid breeding in crops. Hybrid rice based on the two-line system using PGMS and TGMS lines has been successfully developed and applied widely in agriculture. However, the molecular mechanism underlying the control of PGMS and TGMS remains obscure. In this study, we mapped and cloned a major locus, p/tms12-1 (photo- or thermo-sensitive genic male sterility locus on chromosome 12), which confers PGMS in the japonica rice line Nongken 58S (NK58S) and TGMS in the indica rice line Peiai 64S (PA64S, derived from NK58S). A 2.4-kb DNA fragment containing the wild-type allele P/TMS12-1 was able to restore the pollen fertility of NK58S and PA64S plants in genetic complementation. P/TMS12-1 encodes a unique noncoding rna, which produces a 21-nucleotide small rna that we named osa-smR5864w. A substitution of C-to-G in p/tms12-1, the only polymorphism relative to P/TMS12-1, is present in the mutant small rna, namely osa-smR5864m. Furthermore, overexpression of a 375-bp sequence of P/TMS12-1 in transgenic NK58S and PA64S plants also produced osa-smR5864w and restored pollen fertility. The small rna was expressed preferentially in young panicles, but its expression was not markedly affected by different day lengths or temperatures. Our results reveal that the point mutation in p/tms12-1, which probably leads to a loss-of-function for osa-smR5864m, constitutes a common cause for PGMS and TGMS in the japonica and indica lines, respectively. Our findings thus suggest that this noncoding small rna gene is an important regulator of male development controlled by cross-talk between the genetic networks and environmental conditions.

关键词： rice PGMS TGMS noncoding rna small rna

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Structure of noncoding rna is a determinant of function of rna binding proteins in transcriptional regulation

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CELL AND BIOSCIENCE 2012年第1期2卷 1-1页

作者： Oyoshi, Takanori Kurokawa, Riki Saitama Med Univ Div Gene Struct Hidaka Saitama 3501241 Japan Saitama Med Univ Funct Res Ctr Genom Med Hidaka Saitama 3501241 Japan Shizuoka Univ Grad Sch Sci Fac Sci Dept Chem Shizuoka 4228529 Japan

The majority of the noncoding regions of mammalian genomes have been found to be transcribed to generate noncoding rnas (ncrnas), resulting in intense interest in their biological roles. During the past decade, numerous ncrnas and aptamers have been identified as regulators of transcription. 6S rna, first described as a ncrna in E. coli, mimics an open promoter structure, which has a large bulge with two hairpin/stalk structures that regulate transcription through interactions with rna polymerase. B2 rna, which has stem-loops and unstructured single-stranded regions, represses transcription of mrna in response to various stresses, including heat shock in mouse cells. The interaction of TLS (translocated in liposarcoma) with CBP/p300 was induced by ncrnas that bind to TLS, and this in turn results in inhibition of CBP/p300 histone acetyltransferase (HAT) activity in human cells. Transcription regulator EWS (Ewing's sarcoma), which is highly related to TLS, and TLS specifically bind to G-quadruplex structures in vitro. The carboxy terminus containing the Arg-Gly-Gly (RGG) repeat domains in these proteins are necessary for cis-repression of transcription activation and HAT activity by the N-terminal glutamine-rich domain. Especially, the RGG domain in the carboxy terminus of EWS is important for the G-quadruplex specific binding. Together, these data suggest that functions of EWS and TLS are modulated by specific structures of ncrnas.

关键词： noncoding rna EWS TLS B2 rna G-quadruplex TERRA

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CENP-B promotes the centromeric localization of ZFAT to control transcription of noncoding rna

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JOUrnaL OF BIOLOGICAL CHEMISTRY 2021年第4期297卷 101213-101213页

作者： Ishikura, Shuhei Yoshida, Kazumasa Hashimoto, Sayuri Nakabayashi, Kazuhiko Tsunoda, Toshiyuki Shirasawa, Senji Fukuoka Univ Dept Cell Biol Fac Med Fukuoka Japan Fukuoka Univ Ctr Adv Mol Med Fukuoka Japan Natl Res Inst Child Hlth & Dev Dept Maternal Fetal Biol Tokyo Japan

The centromere is a chromosomal locus that is essential for the accurate segregation of chromosomes during cell division. Transcription of noncoding rna (ncrna) at the centromere plays a crucial role in centromere function. The zinc -finger transcriptional regulator ZFAT binds to a specific 8-bp DNA sequence at the centromere, named the ZFAT box, to control ncrna transcription. However, the precise molecular mechanisms by which ZFAT localizes to the centromere remain elusive. Here we show that the centromeric protein CENP-B is required for the centromeric localization of ZFAT to regulate ncrna transcription. The ectopic expression of CENP-B induces the accumulation of both endogenous and ectopically expressed ZFAT protein at the centromere in human cells, suggesting that the centromeric localization of ZFAT requires the presence of CENP-B. Coimmunoprecipitation analysis reveals that ZFAT interacts with the acidic domain of CENP-B, and depletion of endogenous CENP-B reduces the centromeric levels of ZFAT protein, further supporting that CENP-B is required for the centromeric localization of ZFAT. In addition, knockdown of CENP-B significantly decreased the expression levels of ncrna at the centromere where ZFAT regulates the transcription, suggesting that CENP-B is involved in the ZFAT-regulated centromeric ncrna transcription. Thus, we concluded that CENP-B contributes to the establishment of the centromeric localization of ZFAT to regulate ncrna transcription.

关键词： centromere transcription regulation protein-protein interaction zinc finger DNA binding protein CENP-B noncoding rna ZFAT

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Death domain-associated protein DAXX regulates noncoding rna transcription at the centromere through the transcription regulator ZFAT

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JOUrnaL OF BIOLOGICAL CHEMISTRY 2022年第11期298卷 102528页

作者： Ishikura, Shuhei Yoshida, Kazumasa Tsunoda, Toshiyuki Shirasawa, Senji Fukuoka Univ Fac Med Dept Cell Biol Fukuoka Japan Fukuoka Univ Res Inst Adv Mol Med Fukuoka Japan

The centromere is an essential chromosomal structure for faithful chromosome segregation during cell division. No protein-coding genes exist at the centromeres, but centromeric DNA is actively transcribed into noncoding rna (ncrna). This centromeric transcription and its ncrna products play important roles in centromere functions. We previously re-ported that the transcriptional regulator ZFAT (zinc -finger protein with AT hook) plays a pivotal role in ncrna tran-scription at the centromere;however, it was unclear how ZFAT involvement was regulated. Here, we show that the death domain-associated protein (DAXX) promotes centromeric localization of ZFAT to regulate ncrna transcription at the centromere. Coimmunoprecipitation analysis of endogenous proteins clearly reveals that DAXX interacts with ZFAT. In addition, we show that ectopic coexpression of ZFAT with DAXX increases the centromeric levels of both ZFAT and ncrna, compared with ectopic expression of ZFAT alone. On the other hand, we found that sirna-mediated depletion of DAXX decreases the centromeric levels of both ZFAT and ncrna in cells ectopically expressing ZFAT. These results suggest that DAXX promotes the centromeric localization of ZFAT and ZFAT-regulated centromeric ncrna transcription. Furthermore, we demonstrate that depletion of endogenous DAXX protein is sufficient to cause a decrease in the ncrna levels at the centromeres of chromosomes 17 and X in which ZFAT regulates the transcription, indicating a physiological significance of DAXX in ZFAT-regulated centromeric ncrna transcription. Taken together, these results demonstrate that DAXX regulates centromeric ncrna transcription through ZFAT.

关键词： centromere transcription regulation protein–protein interaction zinc finger DNA-binding protein DAXX noncoding rna ZFAT

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Towards a comprehensive pipeline to identify and functionally annotate long noncoding rna (lncrna)

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COMPUTERS IN BIOLOGY AND MEDICINE 2020年 127卷 104028-104028页

作者： Ramakrishnaiah, Yashpal Kuhlmann, Levin Tyagi, Sonika Monash Univ Fac Informat Technol Clayton Vic 3800 Australia Monash Univ Sch Biol Sci Clayton Vic 3800 Australia Monash Univ Monash eRes Ctr Clayton Vic 3800 Australia

Long noncoding rnas (lncrnas) are implicated in various genetic diseases and cancer, attributed to their critical role in gene regulation. They are a divergent group of rnas and are easily differentiated from other types with unique characteristics, functions, and mechanisms of action. In this review, we provide a list of some of the prominent data repositories containing lncrnas, their interactome, and predicted and validated disease associations. Next, we discuss various wet-lab experiments formulated to obtain the data for these repositories. We also provide a critical review of in silico methods available for the identification purpose and suggest techniques to further improve their performance. The bulk of the methods currently focus on distinguishing lncrna transcripts from the coding ones. Functional annotation of these transcripts still remains a grey area and more efforts are needed in that space. Finally, we provide details of current progress, discuss impediments, and illustrate a roadmap for developing a generalized computational pipeline for comprehensive annotation of lncrnas, which is essential to accelerate research in this area.

关键词： noncoding rna lncrna Gene regulation Epigenomics Bioinformatics Machine learning ANN

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Advances and challenges in studying noncoding rna regulation of drug metabolism and development of rna therapeutics

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BIOCHEMICAL PHARMACOLOGY 2019年 169卷 113638-000页

作者： Ning, Baitang Yu, Dianke Yu, Ai-Ming US FDA Natl Ctr Toxicol Res Jefferson AR 72079 USA Qingdao Univ Sch Publ Hlth Qingdao Peoples R China Univ Calif Davis Dept Biochem & Mol Med Sch Med 2700 Stockton BlvdSuite 2132 Sacramento CA 95817 USA

Accumulating evidence has demonstrated that genome-derived noncoding rnas (ncrnas) play important roles in modulating inter-individual variations observed in drug metabolism and disposition by controlling the expression of genes coding drug metabolizing enzymes and transporters (DMETs) and relevant nuclear receptors (NRs). With the understanding of novel ncrna regulatory mechanisms and significance in the control of disease initiation and progression, rna-based therapies are under active investigation that may expand the druggable targets from conventional proteins to rnas and the genome for the treatment of human diseases. Herein we provide an overview of research strategies, approaches and their limitations in biochemical and pharmacological studies pertaining to ncrna functions in the regulation of drug and nutrient metabolism and disposition, and discussion on the promise and challenges in developing rna therapeutics.

关键词： noncoding rna Pharmacoepigenetics Drug metabolizing enzymes and transporters rna therapeutics Bioengineered rna Drug development

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The striatal long noncoding rna Abhd11os is neuroprotective against an N-terminal fragment of mutant huntingtin in vivo

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NEUROBIOLOGY OF AGING 2015年第3期36卷 1601.e7-1601.e16页

作者： Francelle, Laetitia Galvan, Laurie Gaillard, Marie-Claude Petit, Fanny Bernay, Benoit Guillermier, Martine Bonvento, Gilles Dufour, Noelle Elalouf, Jean-Marc Hantraye, Philippe Deglon, Nicole de Chaldee, Michel Brouillet, Emmanuel CEA DSV I2BM Mol Imaging Res Ctr MIRCen F-92265 Fontenay Aux Roses France Univ Paris 11 UMR 9199 Neurodegenerat Dis Lab CEACNRS Fontenay Aux Roses France CEA iBiTecS Gif Sur Yvette France CNRS FRE 3377 Gif Sur Yvette France Univ Paris 11 FRE 3377 Gif Sur Yvette France

A large number of gene products that are enriched in the striatum have ill-defined functions, although they may have key roles in age-dependent neurodegenerative diseases affecting the striatum, especially Huntington disease (HD). In the present study, we focused on Abhd11os, (called ABHD11-AS1 in human) which is a putative long noncoding rna (lncrna) whose expression is enriched in the mouse striatum. We confirm that despite the presence of 2 small open reading frames (ORFs) in its sequence, Abhd11os is not translated into a detectable peptide in living cells. We demonstrate that Abhd11os levels are markedly reduced in different mouse models of HD. We performed in vivo experiments in mice using lentiviral vectors encoding either Abhd11os or a small hairpin rna targeting Abhd11os. Results show that Abhd11os overexpression produces neuroprotection against an N-terminal fragment of mutant huntingtin, whereas Abhd11os knockdown is protoxic. These novel results indicate that the loss lncrna Abhd11os likely contribute to striatal vulnerability in HD. Our study emphasizes that lncrna may play crucial roles in neurodegenerative diseases. (C) 2015 The Authors. Published by Elsevier Inc.

关键词： Huntington disease Striatum Neurodegeneration noncoding rna Neuroprotection Gene regulation

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The Long noncoding rna CCAT2 Induces Chromosomal Instability Through BOP1-AURKB Signaling

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GASTROENTEROLOGY 2020年第6期159卷 2146-2195页

作者： Chen, Baoqing Dragomir, Mihnea P. Fabris, Linda Bayraktar, Recep Knutsen, Erik Liu, Xu Tang, Changyan Li, Yongfeng Shimura, Tadanobu Ivkovic, Tina Catela De los Santos, Mireia Cruz Anfossi, Simone Shimizu, Masayoshi Shah, Maitri Y. Ling, Hui Shen, Peng Multani, Asha S. Pardini, Barbara Burks, Jared K. Katayama, Hiroyuki Reineke, Lucas C. Huo, Longfei Syed, Muddassir Song, Shumei Ferracin, Manuela Oki, Eiji Fromm, Bastian Ivan, Cristina Bhuvaneshwar, Krithika Gusev, Yuriy Mimori, Koshi Menter, David Sen, Subrata Matsuyama, Takatoshi Uetake, Hiroyuki Vasilescu, Catalin Kopetz, Scott Parker-Thornburg, Jan Taguchi, Ayumu Hanash, Samir M. Girnita, Leonard Slaby, Ondrej Goel, Ajay Varani, Gabriele Gagea, Mihai Li, Chunlai Ajani, Jaffer A. Calin, George A. Univ Texas MD Anderson Canc Ctr Dept Expt Therapeut Houston TX 77030 USA Sun Yat Sen Univ State Key Lab Oncol South China Collaborat Innovat Ctr Canc Med Dept Radiat OncolCanc Ctr Guangzhou Guangdong Peoples R China Sichuan Univ West China Hosp Dept Thorac Oncol Canc Ctr Chengdu Sichuan Peoples R China Sichuan Univ West China Hosp State Key Lab Biotherapy Chengdu Sichuan Peoples R China Carol Davila Univ Med & Pharm Dept Gen Surg Fundeni Clin Hosp Bucharest Romania Arctic Univ Norway Dept Med Biol Fac Hlth Sci Tromso Norway Xi An Jiao Tong Univ Affiliated Hosp 1 Dept Thorac Surg Xian Peoples R China Univ Washington Dept Chem Seattle WA 98195 USA Ctr Gastrointestinal Res Dallas TX USA Baylor Univ Med Ctr Baylor Scott & White Res Inst Ctr Translat Genom & OncolCharles Sammons Canc C Dallas TX USA Masaryk Univ Cent European Inst Technol Brno Czech Republic Southern Med Univ Nanfang Hosp Dept Oncol Guangzhou Peoples R China Univ Texas MD Anderson Canc Ctr Dept Genet Houston TX 77030 USA Univ Texas MD Anderson Canc Ctr Dept Leukemia Houston TX 77030 USA Univ Texas MD Anderson Canc Ctr Dept Clin Canc Prevent Houston TX 77030 USA Baylor Coll Med Dept Neurosci Houston TX 77030 USA Univ Texas MD Anderson Canc Ctr Dept Gastrointestinal Med Oncol Houston TX 77030 USA Univ Bologna Dept Expt Diagnost & Specialty Med Bologna Italy Kyushu Univ Grad Sch Med Sci Dept Surg & Sci Fukuoka Japan Stockholm Univ Wenner Gren Inst Dept Mol Biosci Sci Life Lab Stockholm Sweden Oslo Univ Hosp Norwegian Radium Hosp Inst Canc Res Dept Tumor Biol Oslo Norway Univ Texas MD Anderson Canc Ctr Ctr RNA Interference & Noncoding RNAs Houston TX 77030 USA Georgetown Univ Innovat Ctr Biomed Informat Washington DC USA Kyushu Univ Beppu Hosp Dept Surg Beppu Oita Japan Univ Texas MD Anderson Canc Ctr Dept Translat Mol Pathol Houston TX 77030 USA Tokyo Med & Dent Univ Grad Sch Med Dept Gastroenterol Surg Tokyo Japan Tokyo Med & Dent Univ Grad Sch Dept Sp

BACKGROUND & AIMS: Chromosomal instability (CIN) is a carcinogenesis event that promotes metastasis and resistance to therapy by unclear mechanisms. Expression of the colon cancer-associated transcript 2 gene (CCAT2), which encodes a long noncoding rna (lncrna), associates with CIN, but little is known about how CCAT2 lncrna regulates this cancer enabling characteristic. METHODS: We performed cytogenetic analysis of colorectal cancer (CRC) cell lines (HCT116, KM12C/SM, and HT29) overexpressing CCAT2 and colon organoids from C57BL/6N mice with the CCAT2 transgene and without (controls). CRC cells were also analyzed by immunofluorescence microscopy, g-H2AX, and senescence assays. CCAT2 transgene and control mice were given azoxymethane and dextran sulfate sodium to induce colon tumors. We performed gene expression array and mass spectrometry to detect downstream targets of CCAT2 lncrna. We characterized interactions between CCAT2 with downstream proteins using MS2 pull-down, rna immunoprecipitation, and selective 20-hydroxyl acylation analyzed by primer extension analyses. Downstream proteins were overexpressed in CRC cells and analyzed for CIN. Gene expression levels were measured in CRC and non-tumor tissues from 5 cohorts, comprising more than 900 patients. RESULTS: High expression of CCAT2 induced CIN in CRC cell lines and increased resistance to 5-fluorouracil and oxaliplatin. Mice that expressed the CCAT2 transgene developed chromosome abnormalities, and colon organoids derived from crypt cells of these mice had a higher percentage of chromosome abnormalities compared with organoids from control mice. The transgenic mice given azoxymethane and dextran sulfate sodium developed more and larger colon polyps than control mice given these agents. Microarray analysis and mass spectrometry indicated that expression of CCAT2 increased expression of genes involved in ribosome biogenesis and protein synthesis. CCAT2 lncrna interacted directly with and stabilized BOP1 ribo

关键词： MSS Aneuploidy Tumorigenesis noncoding rna

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Long noncoding rna expression in acute lymphoblastic leukemia: A systematic review

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CRITICAL REVIEWS IN ONCOLOGY HEMATOLOGY 2024年 196卷 104290-104290页

作者： Lobo-Alves, Sara Cristina de Oliveira, Liana Alves Kretzschmar, Gabriela Canalli Valengo, Andressa Eloisa Rosati, Roberto Inst Pesquisa Pele Pequeno Principe Av Silva Jardim 1632 BR-80250060 Curitiba PR Brazil Fac Pequeno Principe Av Iguacu 333 BR-80230020 Curitiba PR Brazil Natl Sci & Technol Inst Childrens Canc Biol & Pedi BR-90035003 Porto Alegre RS Brazil Av Silva Jardim 1632 BR-80250060 Curitiba PR Brazil

Long noncoding rnas (lncrnas), as gene expression modulators, are potential players in Acute Lymphoblastic Leukemia (ALL) pathogenesis. We systematically explored current literature on lncrna expression in ALL to identify lncrnas consistently reported as differentially expressed (DE) either in ALL versus controls or between ALL subtypes. By comparing articles that provided global expression data for DE lncrnas in the ETV6::RUNX1- positive ALL subtype, we identified four DE lncrnas in three independent studies (two versus other subtypes and one versus controls), showing concordant expression of LINC01013, CRNDE and lnc-KLF7-1. Additionally, LINC01503 was consistently downregulated on ALL versus controls. Within RT-qPCR studies, twelve lncrna were DE in more than one source. Thus, several lncrnas were supported as DE in ALL by multiple sources, highlighting their potential role as candidate biomarkers or therapeutic targets. Finally, as lncrna annotation is rapidly expanding, standardization of reporting and nomenclature is urgently needed to improve data verifiability and compilation.

关键词： Long noncoding rna noncoding rna Acute lymphoblastic leukemia Leukemia Differential gene expression Transcriptome LINC01013 CRNDE

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