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Marked for Life: Epigenetic Effects of Endocrine Disrupting Chemicals

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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NoRC silences rrna genes, telomeres, and centromeres

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CELL CYCLE 2014年第4期13卷 493-494页

作者： Postepska-Igielska, Anna Grummt, Ingrid DKFZ ZMBH Alliance German Canc Res Ctr Div Mol Biol Cell 2 Heidelberg Germany

Constitutive heterochromatin, initially perceived as genomic junk, has been shown to be a dynamic, transcriptionally active compartment that is important for genome stability. As a structural hallmark of repetitive sequences, constitutive heterochromatin secures genomic integrity by counteracting mutagenic rearrangement caused by excessive homologous recombination and/or uncontrolled transposition events. In human cells, major heterochromatin clusters are located at centromeres, telomeres, and rrna genes (rDNA) on the short arm of acrocen-tric chromosomes. Despite their diverse biological functions, telomeres, centromeres, and rrna genes share characteristic heterochromatic features that are indispensible for proper nuclear structure and function. Regarding the mechanism underlying heterochromatin formation at repetitive loci, previous studies have shown that the switch between the active and silent state of rrna genes is mediated by NoRC, a chromatin remodeling complex comprising the ATPase SNF2h and a large subunit, termed TIP5. Targeting NoRC to rDNA triggers the establishment of heterochromatic histone modifications and de novo DNA methylation, leading to chromatin compaction and transcrip-tionai silencing of a fraction of rDNA repeats. Thus, NoRC consolidates several enzymatic processes, providing a platform for the recruitment of chromatin modifiers that establish repressive chromatin structure at the rDNA promoter.

关键词： NoRC noncoding rna genome stability telomeres repetitive elements rrna genes centromeres heterochromatin chromatin modifying enzymes

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Emerging role of long noncoding rnas in autoimmune diseases

Emerging role of long noncoding RNAs in autoimmune diseases

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2015年度安徽省流行病与卫生统计学学术论坛

作者： Guo-Cui Wu Hai-Feng Pan Rui-Xue Leng De-Guang Wang Xiang-Pei Li Xiao-Mei Li Dong-Qing Ye Department of Epidemiology and Biostatistics School of Public HealthAnhui Medical University Anhui Provincial Laboratory of Population Health and Major Disease Screening and Diagnosis Anhui Medical University Department of Nephrology The Second Affiliated Hospital of Anhui Medical University Department of Rheumatology and Immunology Anhui Provincial HospitalAffiliated to Anhui Medical University

Long noncoding rna(lncrna),with size larger than 200 nucleotides,is a new class of noncoding *** evidence has revealed that lnc rnas play a key role in the regulation of immunological functions and ***,we review the recent findings of lnc rna regulation in immune functions and in the development of autoimmunity and autoimmune *** addition,we focus on the involvement of lnc rna regulation in innate and adaptive immune responses,immune cell development,and differential expression of lnc rnas in autoimmune diseases,including systemic lupus erythematosus(SLE),rheumatoid arthritis(RA),type 1 diabetes mellitus(T1DM),multiple sclerosis(MS),autoimmune thyroid disease(AITD),psoriasis,polymyositis/dermatomyositis(PM/DM) and Crohn's disease(CD).

关键词： lncrna noncoding rna Immune function Autoimmunity Autoimmune disease

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A recombinase-based palindrome generator capable of producing randomized shrna libraries

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JOUrnaL OF BIOTECHNOLOGY 2009年第2期143卷 79-84页

作者： Nichols, Mark Steinman, Richard A. 2 26 Hillman Canc Ctr Dept Pharmacol Pittsburgh PA 15213 USA Univ Pittsburgh Sch Med Dept Med Pittsburgh PA USA Univ Pittsburgh Inst Canc Pittsburgh PA USA

Short hairpin rna (shrna)-expressing vectors have been shown stably to knock-down directed targets through rna interference (rnai). rnai has emerged as a powerful tool for reverse genetic screens by assaying cellular phenotypes after exposure to libraries of pooled shrnas directed against all or a subset of cellular mrnas. Recently, noncoding rnas have been recognized as major arbiters of cellular phenotypes. The scope and diversity of noncoding rnas greatly enlarge the target pool for reversible genetic screens and underscore the desirability as screening tools of complex rnai libraries, such as randomized rnai libraries. We describe a novel approach to generate randomized shrnas that takes advantage of a stable plasmid intermediate that arises in a FLP recombinase system. The ability of this system to generate randomized palindromes represents a new technology for shrna generation including random shrnas that cannot be produced synthetically. We describe this plasmid system and its use in generating randomized shrnas from input 20-bp oligomers, and validate the functionality of a shrna produced using this approach to knock-down estrogen receptor alpha expression. (C) 2009 Elsevier B.V. All rights reserved.

关键词： FLP recombinase noncoding rna Randomized libraries Interfering rna

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Diagnostic, functional, and therapeutic roles of microrna in allergic diseases

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JOUrnaL OF ALLERGY AND CLINICAL IMMUNOLOGY 2013年第1期132卷 3-13页

作者： Lu, Thomas X. Rothenberg, Marc E. Univ Cincinnati Coll Med Cincinnati Childrens Hosp Med Ctr Div Allergy & Immunol Cincinnati OH 45221 USA Univ Cincinnati Coll Med Cincinnati Childrens Hosp Med Ctr Med Scientist Training Program Cincinnati OH 45221 USA

Allergic inflammation is accompanied by the coordinated expression of a myriad of genes and proteins that initiate, sustain, and propagate immune responses and tissue remodeling. Micrornas (mirnas) are a class of short single-stranded rna molecules that posttranscriptionally silence gene expression and have been shown to fine-tune gene transcriptional networks because single mirnas can target hundreds of genes. Considerable attention has been focused on the key role of mirnas in regulating homeostatic immune architecture and acquired immunity. Recent studies have identified mirna profiles in multiple allergic inflammatory diseases, including asthma, eosinophilic esophagitis, allergic rhinitis, and atopic dermatitis. Specific mirnas have been found to have critical roles in regulating key pathogenic mechanisms in allergic inflammation, including polarization of adaptive immune responses and activation of T cells (eg, miR-21 and miR-146), regulation of eosinophil development (eg, miR-21 and miR-223), and modulation of IL-13-driven epithelial responses (eg, miR-375). This review discusses recent advances in our understanding of the expression and function of mirnas in patients with allergic inflammation, their role as disease biomarkers, and perspectives for future investigation and clinical utility.

关键词： Allergy microrna noncoding rna asthma eosinophilic esophagitis atopic dermatitis allergic rhinitis eosinophils inflammation biomarkers

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Distribution of the MCS4 rna genes in mycoplasmas belonging to the Mycoplasma mycoides cluster

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GENE 2003年第1-2期314卷 149-155页

作者： Ushida, C Yoshida, A Miyakawa, Y Ara, Y Muto, A Hirosaki Univ Fac Agr & Life Sci Dept Biochem & Biotechnol Hirosaki Aomori 0368561 Japan

MCS4 rna is one of the small stable rnas found in Mycoplasma capricolum subsp. capricolum type strain California kid. This rna has a sequence similarity to that of eukaryotic U6 snrna. There are two genes encoding MCS4 rna, designated mcs4a and mcs4b, in the genome. Homologous sequences of these genes were not found in databases of other bacterial sequences. We searched for MCS4 rna and its genes in other bacteria by PCR and hybridization techniques. The results strongly suggested that this rna exists only in a limited species of mycoplasmas belonging to the Mycoplasma mycoides cluster. (C) 2003 Elsevier B.V. All rights reserved.

关键词： small rna noncoding rna bacteria Mycoplasma capricolum

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The role of rna processing and regulation in metastatic dormancy

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SEMINARS IN CANCER BIOLOGY 2022年第0期78卷 23-34页

作者： Parker, Kimberly A. Robinson, Nathaniel J. Schiemann, William P. Case Western Reserve Univ Dept Pharmacol Cleveland OH 44106 USA Case Western Reserve Univ Case Comprehens Canc Ctr Wolstein Res Bldg2103 Cornell Rd Cleveland OH 44106 USA

Tumor dormancy is a major contributor to the lethality of metastatic disease, especially for cancer patients who develop metastases years-to-decades after initial diagnosis. Indeed, tumor cells can disseminate during early disease stages and persist in new microenvironments at distal sites for months, years, or even decades before initiating metastatic outgrowth. This delay between primary tumor remission and metastatic relapse is known as "dormancy," during which disseminated tumor cells (DTCs) acquire quiescent states in response to intrinsic (i.e., cellular) and extrinsic (i.e., microenvironmental) signals. Maintaining dormancy-associated phenotypes requires DTCs to activate transcriptional, translational, and post-translational mechanisms that engender cellular plasticity. rna processing is emerging as an essential facet of cellular plasticity, particularly with respect to the initiation, maintenance, and reversal of dormancy-associated phenotypes. Moreover, dysregulated rna processing, particularly that associated with alternative rna splicing and expression of noncoding rnas (ncrnas), can occur in DTCs to mediate intrinsic and extrinsic metastatic dormancy. Here we review the pathophysiological impact of alternative rna splicing and ncrnas in promoting metastatic dormancy and disease recurrence in human cancers.

关键词： Alternative splicing Cancer stem cells Epithelial-mesenchymal transition lncrna Metastatic dormancy microrna noncoding rna rna processing

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Dysfunctional Gastric Emptying With Down-regulation of Muscle-Specific Micrornas in Helicobacter pylori-Infected Mice

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GASTROENTEROLOGY 2011年第1期140卷 189-198页

作者： Saito, Yoshimasa Suzuki, Hidekazu Tsugawa, Hitoshi Suzuki, Sachiko Matsuzaki, Juntaro Hirata, Kenro Hibi, Toshifumi Keio Univ Sch Med Div Gastroenterol & Hepatol Dept Internal MedShinjuku Ku Tokyo 1608582 Japan

BACKGROUND & AIMS: Little is known about the pathogenic mechanisms of functional dyspepsia. We investigated the role of micrornas (mirnas) in gastric motility disorders associated with Helicobacter pylori infection. METHODS: Male C57BL/6 mice were infected with H pylori. After long-term infection, gastric emptying was examined and compared with that of uninfected mice (controls). The mirna expression profile was analyzed by mirna microarray and quantitative reverse-transcriptase polymerase chain reaction. The results obtained from the animal study were confirmed by in vitro experiments. RESULTS: Gastric emptying was significantly accelerated in mice after chronic infection with H pylori. Histologic examination showed that the muscular layers of the stomachs of H pylori-infected mice were significantly thickened. The mirna expression profile revealed that the muscle-specific mirnas miR-1 and miR-133 were significantly down-regulated in the stomachs after long-term infection with H pylori. However, expression of histone deacetylase 4 and serum response factor, which are reported target genes of miR-1 and miR-133, increased. Down-regulation of miR-1 and miR-133 and increased cell proliferation were observed in C2C12 mouse myoblast cells after coculture with H pylori. CONCLUSIONS: Chronic infection with H pylori down-regulates expression of muscle-specific mirnas and up-regulates expression of histone deacetylase 4 and serum response factor. These might cause hyperplasia in the muscular layer of the stomach and dysfunction in gastric emptying. These findings provide insight into the molecular pathogenesis of gastric motility disorders, including functional dyspepsia.

关键词： Functional Gastrointestinal Disorder noncoding rna Muscle Cell Liquid Gastric Emptying

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Ro60 and Y rnas: structure, functions, and roles in autoimmunity

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CRITICAL REVIEWS IN BIOCHEMISTRY AND MOLECULAR BIOLOGY 2019年第2期54卷 133-152页

作者： Boccitto, Marco Wolin, Sandra L. NCI RNA Biol Lab Ctr Canc Res Frederick MD 21702 USA

Ro60, also known as SS-A or TROVE2, is an evolutionarily conserved rna-binding protein that is found in most animal cells, approximately 5% of sequenced prokaryotic genomes and some archaea. Ro60 is present in cells as both a free protein and as a component of a ribonucleoprotein complex, where its best-known partners are members of a class of noncoding rnas called Y rnas. Structural and biochemical analyses have revealed that Ro60 is a ring-shaped protein that binds Y rnas on its outer surface. In addition to Y rnas, Ro60 binds misfolded and aberrant noncoding rnas in some animal cell nuclei. Although the fate of these defective Ro60-bound noncoding rnas in animal cells is not well-defined, a bacterial Ro60 ortholog functions with 3 to 5 exoribonucleases to assist structured rna degradation. Studies of Y rnas have revealed that these rnas regulate the subcellular localization of Ro60, tether Ro60 to effector proteins and regulate the access of other rnas to its central cavity. As both mammalian cells and bacteria lacking Ro60 are sensitized to ultraviolet irradiation, Ro60 function may be important during exposure to some environmental stressors. Here we summarize the current knowledge regarding the functions of Ro60 and Y rnas in animal cells and bacteria. Because the Ro60 RNP is a clinically important target of autoantibodies in patients with rheumatic diseases such as Sjogren's syndrome, systemic lupus erythematosus, and neonatal lupus, we also discuss potential roles for Ro60 RNPs in the initiation and pathogenesis of systemic autoimmune rheumatic disease.

关键词： Ro60 Y rna Rsr autoantigen noncoding rna rna degradation

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5’tirna-Pro-TGG,a novel trna halve,promotes oncogenesis in sessile serrated lesions and serrated pathway of colorectal cancer

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World Journal of Gastrointestinal Oncology 2023年第6期15卷 1005-1018页

作者： Xin-Yuan Wang Yu-Jie Zhou Hai-Ying Chen Jin-Nan Chen Shan-Shan Chen Hui-Min Chen Xiao-Bo Li Division of Gastroenterology and Hepatology Renji HospitalShanghai Jiaotong University School of MedicineShanghai 200000China Department of Spleen and Stomach and Rheumatology Affiliated Traditional Chinese Medicine Hospital of Southwest Medical UniversityLuzhou 646000Sichuan ProvinceChina

BACKGROUND Transfer rna(trna)-derived small rnas(tsrnas)are small fragments that form when trnas *** halves(tirnas),a subcategory of tsrna,are involved in the oncogenic processes of many ***,their specific role in sessile serrated lesions(SSLs),a precancerous lesion often observed in the colon,has not yet been *** To identify SSL-related tirnas and their potential role in the development of SSLs and serrated pathway of colorectal cancer(CRC).METHODS Small-rna sequencing was conducted in paired SSLs and their adjacent normal control(NC)*** expression levels of five SSL-related tirnas were validated by q-polymerase chain *** counting kit-8 and wound healing assays were performed to detect cell proliferation and *** target genes and sites of tirna-1:33-Pro-TGG-1(5′tirna-Pro-TGG)were predicted by TargetScan and miRanda ***-associated and immune-related pathways were analyzed by single-sample gene set enrichment *** analyses were performed to establish the roles of 5′tirna-Pro-TGG based on the target *** In total,we found 52 upregulated tsrnas and 28 downregulated tsrnas in SSLs compared to *** expression levels of tirna-1:33-Gly-CCC-2,tirna-1:33-Pro-TGG-1,and tirna-1:34-Thr-TGT-4-M25′tirnas were higher in SSLs than those in NC,while that of 5′tirna-Pro-TGG was associated with the size of *** was demonstrated that 5′tirnaPro-TGG promoted cell proliferation and migration of RKO cell in ***,heparanase 2(HPSE2)was identified as a potential target gene of 5′*** lower expression was associated with a worse prognosis in ***,lower expression of HPSE2 was observed in SSLs compared to normal controls or conventional adenomas and in BRAF-mutant CRC compared to BRAF-wild *** analyses revealed that its low expression was associated with a low interferonγresponse and also with many metabolic pathways such as riboflavin,retinol,and cy

关键词： noncoding rna trna halves Sessile serrated lesions Colon cancer Serrated pathway

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