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From Waddington's epigenetic landscape to small noncoding rna: some important milestones in the history of epigenetics research

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TOXICOLOGY MECHANISMS AND METHODS 2011年第4期21卷 252-274页

作者： Choudhuri, Supratim US FDA Ctr Food Safety & Appl Nutr OFAS DBGNR College Pk MD 20740 USA

The term epigenetics was coined in 1942 by C. H. Waddington in the context of studies on development. Since then, the meaning of epigenetics changed over time. In the beginning, epigenetics was viewed as a phenomenon above and beyond genetics. Epigenetic explanations were invoked when genetics could not explain a phenomenon. From the mid-seventies, the state of understanding started changing. Epigenetics has now morphed from a phenomenon to a branch of science whose molecular underpinnings are well understood. The current state of knowledge of epigenetics has evolved as our understanding of DNA methylation, chromatin modifications, and noncoding rna, and their effects on gene expression increased. At this time in the annals of epigentics research, it is appropriate to revisit some of the important discoveries that have helped advance the field to its current state. This is a very brief review of some early discoveries, and by no means is a complete account of the history of epigenetics. In this review, the early history has also been emphasized in order to underscore the transformation of the science of epigenetics from a phenomenon to a modern field of intense research.

关键词： Epigenetics waddington history epigenetic landscape canalization DNA methylation histone modification noncoding rna

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Cofactors of LIM Domains Associate with Estrogen Receptor α to Regulate the Expression of noncoding rna H19 and Corneal Epithelial Progenitor Cell Function

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JOUrnaL OF BIOLOGICAL CHEMISTRY 2016年第25期291卷 13271-13285页

作者： Klein, Rachel Herndon Stephens, Denise N. Ho, Hsiang Chen, Jefferson K. Salmans, Michael L. Wang, Winnie Yu, Zhengquan Andersen, Bogi Univ Calif Irvine Dept Biol Chem Irvine CA 92697 USA Univ Calif Irvine Dept Med 839 Hlth Sci Dr Irvine CA 92697 USA Univ Calif Irvine Inst Genom & Bioinformat Irvine CA 92697 USA China Agr Univ State Key Labs AgroBiotechnol Coll Biol Sci Beijing 100193 Peoples R China

Cofactors of LIM domain proteins, CLIM1 and CLIM2, are widely expressed transcriptional cofactors that are recruited to gene regulatory regions by DNA-binding proteins, including LIM domain transcription factors. In the cornea, epithelium-specific expression of a dominant negative (DN) CLIM under the keratin 14 (K14) promoter causes blistering, wounding, inflammation, epithelial hyperplasia, and neovascularization followed by epithelial thinning and subsequent epidermal-like differentiation of the corneal epithelium. The defects in corneal epithelial differentiation and cell fate determination suggest that CLIM may regulate corneal progenitor cells and the transition to differentiation. Consistent with this notion, the K14-DN-Clim corneal epithelium first exhibits increased proliferation followed by fewer progenitor cells with decreased proliferative potential. In vivo ChIP-sequencing experiments with corneal epithelium show that CLIM binds to and regulates numerous genes involved in cell adhesion and proliferation, including limbally enriched genes. Intriguingly, CLIM associates primarily with non-LIM homeodomain motifs in corneal epithelial cells, including that of estrogen receptor alpha. Among CLIM targets is the noncoding rna H19 whose deregulation is associated with Silver-Russell and Beckwith-Wiedemann syndromes. We demonstrate here that H19 negatively regulates corneal epithelial proliferation. In addition to cell cycle regulators, H19 affects the expression of multiple cell adhesion genes. CLIM interacts with estrogen receptor alpha at the H19 locus, potentially explaining the higher expression of H19 in female than male corneas. Together, our results demonstrate an important role for CLIM in regulating the proliferative potential of corneal epithelial progenitors and identify CLIM downstream target H19 as a regulator of corneal epithelial proliferation and adhesion.

关键词： cell proliferation epithelial cell estrogen receptor eye gene regulation stem cells coregulators corneal epithelium noncoding rna

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The roles of noncoding rna Rli60 in regulating the virulence of Listeria monocytogenes

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JOUrnaL OF MICROBIOLOGY IMMUNOLOGY AND INFECTION 2016年第4期49卷 502-508页

作者： Peng, Ye-Long Meng, Qing-Ling Qiao, Jun Xie, Kun Chen, Cheng Liu, Tian-Li Hu, Zheng-Xiang Ma, Yu Cai, Xue-Peng Chen, Chuang-Fu Shihezi Univ Coll Anim Sci & Technol North St 4 Shihezi 832003 Xinjiang Peoples R China Chinese Acad Agr Sci Lanzhou Vet Res Inst State Key Lab Vet Etiol Biol Lanzhou Gansu Peoples R China

Background: Listeria monocytogenes (LM) is an important zoonotic foodborne pathogen. noncoding rna (ncrna) has an important role in regulating its virulence. As a member of ncrna, however, the function of Rli60 in regulating LM virulence remain unclear. The aim of this study was to investigate the role of Rli60 in regulating LM virulence. Methods: Using a homologous recombination method, a LM EGD-e rli60 gene deletion strain (LM-Delta rli60) was constructed and compared with a LM EGD-e strain in the following respects: (1) adhesiveness, invasion ability, intracellular survival, proliferation, and transcription of virulence genes in the mouse macrophage cell line RAW264.7;(2) 50% lethal dose (LD50) to the BALB/c mouse;and (3) the amount in the mouse liver and spleen and the effects on pathology of mouse liver, spleen, and kidney after inoculation. Results: The LM-Delta rli60 strain had a significantly higher adhesion rate and lower invasion rate with significantly lower intracellular survival and proliferation rates in the RAW264.7 cell line, compared to the LM EGD-e strain. Inoculation with LM-Delta rli60 strain significantly affected the transcription of virulence genes. The LD50 of LM-Delta rli60 to BALB/c mouse was increased by 2.12 logarithmic magnitude, which indicated that the virulence in LM-Delta rli60 is significantly decreased (p < 0.05). The amount of LM-Delta rli60 in the liver and spleen was significantly lower than the amount of LM EGD-e in these organs (p < 0.05). The pathological damage due to LM-Delta rli60 infection in the mouse liver, spleen, and kidney was lower than the damage due to LM EGD-e infection. Conclusion: This study confirmed that the rli60 deletion could significantly affect LM virulence, adhesion, invasion, survival, and proliferation. This suggests that Rli60 has an important role in regulating LM virulence. Copyright (C) 2014, Taiwan Society of Microbiology. Published by Elsevier Taiwan LLC. This is an open access article under the

关键词： Listeria monocytogenes noncoding rna rli60 gene virulence

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An update on recent methods applied for deciphering the diversity of the noncoding rna genome structure and function

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METHODS 2013年第1期63卷 3-17页

作者： Spicuglia, Salvatore Maqbool, Muhammad Ahmad Puthier, Denis Andrau, Jean-Christophe TAGC F-13288 Marseille 09 France Aix Marseille Univ Marseille France INSERM UMR1090 F-13258 Marseille France Ctr Immunol Marseille Luminy F-13288 Marseille 9 France CNRS UMR6102 Marseille France INSERM U631 F-13258 Marseille France

The explosion of high throughput sequencing technologies marked a turn in our way of understanding the complexity and diversity of the transcriptome, including noncoding transcription dependent on rna polymerase II. Many new ncrna populations were described in recent years, including for example TSS rnas, lincrnas, ernas, PROMPTS and several others. Besides the advances in the average depth coverage of rna-seq experiments, various additional protocols are now available that can be used to address qualitative and quantitative aspects of the noncoding transcriptome complexity and function. In this review, we will focus on methods allowing isolation and characterization of complex rna populations using sequencing based approaches, including conventional strategies already used for coding genome and more specific developments allowing, for example, the study of nascent strand transcription, protein-bound or structured rnas. Crown Copyright (C) 2013 Published by Elsevier Inc. All rights reserved.

关键词： Transcriptome rna-seq noncoding rna GRO-seq rna-PET CLIP-seq

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Transcription Regulation by the noncoding rna SRG1 Requires Spt2-Dependent Chromatin Deposition in the Wake of rna Polymerase II

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MOLECULAR AND CELLULAR BIOLOGY 2011年第6期31卷 1288-1300页

作者： Thebault, Philippe Boutin, Genevieve Bhat, Wajid Rufiange, Anne Martens, Joseph Nourani, Amine Univ Laval Ctr Rech Cancerol LHotel Dieu Quebec CHUQ Quebec City PQ G1R 2J6 Canada Univ Pittsburgh Dept Biol Sci Pittsburgh PA 15260 USA

pt2 is a chromatin component with roles in transcription and posttranscriptional regulation. Recently, we found that Spt2 travels with rna polymerase II (rnaP II), is involved in elongation, and plays important roles in chromatin modulations associated with this process. In this work, we dissect the function of Spt2 in the repression of SER3. This gene is repressed by a transcription interference mechanism involving the transcription of an adjacent intergenic region, SRG1, that leads to the production of a noncoding rna (ncrna). We find that Spt2 and Spt6 are required for the repression of SER3 by SRG1 transcription. Intriguingly, we demonstrate that these effects are not mediated through modulations of the SRG1 transcription rate. Instead, we show that the SRG1 region overlapping the SER3 promoter is occluded by randomly positioned nucleosomes that are deposited behind rnaP II transcribing SRG1 and that their deposition is dependent on the presence of Spt2. Our data indicate that Spt2 is required for the major chromatin deposition pathway that uses old histones to refold nucleosomes in the wake of rnaP II at the SRG1-SER3 locus. Altogether, these observations suggest a new mechanism of repression by ncrna transcription involving a repressive nucleosomal structure produced by an Spt2-dependent pathway following rnaP II passage.

关键词： rna histone rna polymerase II: 9014-24-8 EC 2.7.7.6 noncoding rna Spt6 Spt2 chromatin: deposition transcription regulation posttranscriptional regulation transcription interference mechanism

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Enhancement of the pathogenicity of Staphylococcus aureus strain Newman by a small noncoding rna SprX1

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MEDICAL MICROBIOLOGY AND IMMUNOLOGY 2016年第6期205卷 563-574页

作者： Kathirvel, Manikandan Buchad, Hasmatbanu Nair, Mrinalini Maharaja Sayajirao Univ Baroda Dept Microbiol Vadodara 390002 Gujarat India Maharaja Sayajirao Univ Baroda Ctr Biotechnol Vadodara 390002 Gujarat India

The pathogenesis of Staphylococcus aureus from local infection to systemic dissemination involves a range of virulence factors including structural and secreted products. Among various control mechanisms, small noncoding rnas are involved in the regulation of multiple pathogenicity factors in S. aureus. The srna SprX which is encoded in the pathogenicity island of methicillin-susceptible S. aureus strain Newman and was shown to influence antibiotic resistance previously, upregulated the expression of virulence genes, especially the cell wall-associated clumping factor B (ClfB) and delta hemolysin (Hld). Bioinformatic analysis revealed several multiple mrnas associated with pathogenicity as targets for SprX1, one of the three copies of sprX. Both overexpression and chromosomal disruption of sprX1 supported the scheme of upregulation of clfB and hld expression. Altered expression of SprX1 altered the levels of Hld and ClfB mrnas, hemolysis, clumping of cells, biofilm formation by plate adhesion studies and confocal microscopic analysis as well as infection pathology of modified strains in mice models. ClfB and Hld mrnas interacted directly with SprX1 in in vitro assays. Increased level of the regulatory rna, namely rnaIII, that comprises Hld mrna and also regulates the biofilm formation, indicates that SprX1 may also function through rnaIII for regulating virulence factors. An immunodominant protein, antigen A, was downregulated by SprX1 in two-dimensional electrophoresis. Taken together, these results signify the role of srna SprX in the pathogenicity of S. aureus Newman.

关键词： Staphylococcus Virulence Hemolysin Biofilm noncoding rna

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Identification of putative noncoding rna genes in the Burkholderia cenocepacia J2315 genome

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FEMS MICROBIOLOGY LETTERS 2007年第1期276卷 83-92页

作者： Coenye, Tom Drevinek, Pavel Mahenthiralingam, Eshwar Shah, Shiraz Ali Gill, Ryan T. Vandamme, Peter Ussery, David W. Univ Ghent Lab Farmaceut Microbiol B-9000 Ghent Belgium Cardiff Univ Cardiff Sch Biosci Cardiff Wales Danish Tech Univ Ctr Biol Sequence Anal Lyngby Denmark Univ Colorado Dept Chem Engn Boulder CO 80309 USA

noncoding rna (ncrna) genes are not involved in the production of mrna and proteins, but produce transcripts that function directly as structural or regulatory rnas. In the present study, the presence of ncrna genes in the genome of Burkholderia cenocepacia J2315 was evaluated by combining comparative genomics (alignment-based) and predicted secondary structure approaches. Two hundred and thirteen putative ncrna genes were identified in the B. cenocepacia J2315 genome and upregulated expression of four of these could be confirmed by microarray analysis. Most of the ncrna gene transcripts have a marked predicted secondary structure that may facilitate interaction with other molecules. Several B. cenocepacia J2315 ncrnas seem to be related to previously characterized ncrnas involved in regulation of various cellular processes, while the function of many others remains unknown. The presence of a large number of ncrna genes in this organism may help to explain its complexity, phenotypic variability and ability to survive in a remarkably wide range of environments.

关键词： Burkholderia cenocepacia noncoding rna microarray

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Mutual regulation of noncoding rnas and rna modifications in psychopathology: Potential therapeutic targets for psychiatric disorders?

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PHARMACOLOGY & THERAPEUTICS 2022年 237卷 108254页

作者： Han, Bing Xi, Wen Hong, Yiting Gu, Liyuan Chao, Yue Li, Lu Liu, ChenChen Yang, Li Chao, Jie Yao, Honghong Southeast Univ Sch Med Dept Pharmacol Jiangsu Prov Key Lab Crit Care Med Nanjing 210009 Peoples R China Southeast Univ Sch Med Dept Physiol Jiangsu Prov Key Lab Crit Care Med Nanjing Peoples R China Southeast Univ Minist Educ Inst Life Sci Key Lab Dev Genes & Human Dis Nanjing Peoples R China Nantong Univ Coinnovat Ctr Neuroregenerat Nantong Peoples R China

The human brain is specifically enriched for multiple classes of noncoding rnas (ncrnas) and for particular rna modifications, both of which are increasingly recognized to contribute to the etiology and pathophysiology of psychiatric disorders. Here, we summarize the rapidly developing areas of basic research in brain-specific ncrna biology and the functional and pathological consequences of different rna modifications. In particular, multiple studies have identified mutual regulation between ncrnas and rna modifications. Specifically, rna methylation of ncrnas can regulate their cleavage and maturation, intracellular transport, stability, and ultimately their degradation. Alternatively, ncrnas can affect rna modifications by up- or down-regulating target protein expression or by altering their subcellular distribution, among several other effects. Growing clinical and predinical research attention is currently being focused on exploring the pathological impacts and highly diverse molecular regulatory mechanisms of ncrnas and rna modifications in psychiatric disorders. Here, we review recent findings surrounding the mutual regulation between ncrnas and rna modifications in brain psychopathology. We also discuss advances in basic discovery and dinical translation or therapeutic potential of targeting ncrnas and/or rna modification regulators in psychiatric disorders. (C) 2022 Elsevier Inc. All rights reserved.

关键词： noncoding rna rna modification Mutual regulation Psychiatric disorders Therapeutic target

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Cell detachment rapidly induces changes in noncoding rna expression in human mesenchymal stromal cells

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BIOTECHNIQUES 2019年第6期67卷 286-293页

作者： Della Bella, Elena Stoddart, Martin J. AO Fdn AO Res Inst Davos Switzerland

Aims: To identify differential expression of noncoding rnas after trypsinization in human mesenchymal stromal cells (hMSCs), focusing on mirnas, pirnas and circrnas. Methods: hMSCs from the bone marrow of three donors were collected for rna extraction, either lysed directly in monolayer or trypsinized and lysed within 30 min. Total rna was isolated and sequenced for the evaluation of mirna and pirna expression or rnaseR treated and labeled for circrna array hybridization. RT-qPCR was performed to evaluate the stability of candidate reference genes. Results & conclusions: Alterations in levels of several noncoding rnas are rapidly induced after trypsinization of hMSCs, affecting critical pathways. This should be carefully considered for a proper experimental design.

关键词： cell detachment circular rna human mesenchymal stem cells loss of anchorage microrna noncoding rna piwi-rna reference gene stability rna sequencing trypsinization

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MALAT1- a paradigm for long noncoding rna function in cancer

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JOUrnaL OF MOLECULAR MEDICINE-JMM 2013年第7期91卷 791-801页

作者： Gutschner, Tony Haemmerle, Monika Diederichs, Sven Univ Heidelberg Hosp Helmholtz Univ Grp Mol RNA Biol & Canc German Canc Res Ctr DKFZ Heidelberg Germany Univ Heidelberg Hosp Inst Pathol Heidelberg Germany German Canc Res Ctr D-69120 Heidelberg Germany

The metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a bona fide long noncoding rna (lncrna). MALAT1, also known as nuclear-enriched transcript 2 (NEAT2), was discovered as a prognostic marker for lung cancer metastasis but also has been linked to several other human tumor entities. Recent work established a critical regulatory function of this lncrna in lung cancer metastasis and cell migration. Moreover, MALAT1 is an interesting target for antimetastatic therapy in non-small cell lung carcinoma. Two alternative modes of action have been proposed for MALAT1: regulation of gene expression or alternative splicing. Although the exact mechanism of action in different physiological and pathological conditions still needs to be elucidated, MALAT1 acts as a regulator of gene expression. Although MALAT1 is highly evolutionary conserved in mammals and plays an important role in cancer and metastasis, MALAT1 is not essential for development in a knockout mouse model under normal physiological conditions. Hence, one central question for the future is finding the right stressor and the pathological or environmental condition which requires MALAT1 expression in vivo and entailing its strong evolutionary conservation. Here, we summarize the current knowledge about this important lncrna. We introduce its discovery, biogenesis, and regulation and describe its known functions, mechanisms of action, and interaction partners.

关键词： Cancer Metastasis noncoding rna ncrna Gene regulation Gene therapy

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