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CRISPR Screens to Discover Functional Noncocinc Elements

TRENDS IN GENETICS 2016年第9期32卷 526-529页

作者： Wright, Jason B. Sanjana, Neville E. Broad Inst MIT & Harvard 7 Cambridge Ctr Cambridge MA 02142 USA MIT Dept Biol Engn Dept Brain & Cognit Sci McGovern Inst Brain Res Cambridge MA 02139 USA New York Genome Ctr New York NY 10013 USA NYU Dept Biol Ctr Genom & Syst Biol 550 1St Ave New York NY 10003 USA

A major challenge in genomics is to identify functional elements in the noncoding genome. Recently, pooled clustered regularly interspersed palindromic repeat (CRISPR) mutagenesis screens of noncoding regions have emerged as a novel method for finding elements that impact gene expression and phenotype/disease-relevant biological processes. Here we review and compare different approaches for high-throughput dissection of noncoding elements.

关键词： functional genomics noncoding gene regulation enhancer CRISPR Cas9

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PCBP2基因座位上长非编码RNA的筛选与鉴定

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基础医学与临床 2013年第6期33卷 694-698页

作者：赵阿妮朱丽媛吴朝刘雪梅阴彬张靖中国医学科学院基础医学研究所医学分子生物学国家重点实验室北京100005 河北北方学院病理及病理生理学实验室河北张家口075000

目的从EST鉴定入手利用生物信息学方法筛选验证PCBP2基因内部UC.338基因座位附近的长非编码RNA。方法首先利用生物信息学方法筛选包含内含子转录区域的ESTs,经CPC分析和统计学比较,共筛选到4个(人、鼠各两个)可能的lncRNAs,用PCR方法进... 详细信息

目的从EST鉴定入手利用生物信息学方法筛选验证PCBP2基因内部UC.338基因座位附近的长非编码RNA。方法首先利用生物信息学方法筛选包含内含子转录区域的ESTs,经CPC分析和统计学比较,共筛选到4个(人、鼠各两个)可能的lncRNAs,用PCR方法进行鉴定,克隆到pGEM-T载体测序验证,并用PCR,real-time PCR的方法检测各ESTs在人源细胞系或小鼠不同组织,小鼠发育不同时间点大脑中的表达谱。结果筛选到4个ESTs中有3个ESTs均具有一定的非编码特征,并最终测序正确:1个人源,2个鼠源,并且其中有些lncRNAs具有一定的细胞、组织特异性,有些lncRNAs具有广谱表达模式。结论使用了一种新的寻找lncRNAs的方法,从EST鉴定入手,对现有数据库进行了挖掘。找到了可能在小鼠大脑发育过程中起作用的lncRNAs。

关键词： ESTs 生物信息学分析 long noncoding RNA 筛选鉴定表达谱分析

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A survey of genomic properties for the detection of regulatory polymorphisms

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PLOS COMPUTATIONAL BIOLOGY 2007年第6期3卷 1000-1010页

作者： Montgomery, Stephen B. Griffith, Obi L. Schuetz, Johanna M. Brooks-Wilson, Angela Jones, Steven J. M. British Columbia Canc Agcy Canadas Michael Smith Genome Sci Ctr Vancouver BC V5Z 4E6 Canada

Advances in the computational identification of functional noncoding polymorphisms will aid in cataloging novel determinants of health and identifying genetic variants that explain human evolution. To date, however, the development and evaluation of such techniques has been limited by the availability of known regulatory polymorphisms. We have attempted to address this by assembling, from the literature, a computationally tractable set of regulatory polymorphisms within the ORegAnno database (http://***). We have further used 104 regulatory single-nucleotide polymorphisms from this set and 951 polymorphisms of unknown function, from 2-kb and 152-bp noncoding upstream regions of genes, to investigate the discriminatory potential of 23 properties related to gene regulation and population genetics. Among the most important properties detected in this region are distance to transcription start site, local repetitive content, sequence conservation, minor and derived allele frequencies, and presence of a CpG island. We further used the entire set of properties to evaluate their collective performance in detecting regulatory polymorphisms. Using a 10-fold cross-validation approach, we were able to achieve a sensitivity and specificity of 0.82 and 0.71, respectively, and we show that this performance is strongly influenced by the distance to the transcription start site.

关键词： .Unknown identifying Traits transcription start noncoding PLoS single-nucleotide Gene Regulation Cross-Validation discriminatory CpG Island Genomic Properties Regulatory Polymorphisms ORegAnno local repetitive

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TREAT: Therapeutic RNAs exploration inspired by artificial intelligence technology

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COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL 2022年 20卷 5680-5689页

作者： Luo, Yufan Liu, Liu He, Zihao Zhang, Shanshan Huo, Peipei Wang, Zhihao Jiaxin, Qin Zhao, Lianhe Wu, Yang Zhang, Dongdong Bu, Dechao Chen, Runsheng Zhao, Yi Chinese Acad Sci Inst Comp Technol Res Ctr Ubiquitous Comp Syst Beijing Peoples R China Univ Chinese Acad Sci Beijing 100049 Peoples R China Luoyang Zhongke Informat Ind Res Inst Luoyang Peoples R China Univ Chinese Acad Sci Hwa Mei Hosp Beijing Peoples R China Chinese Acad Sci Ctr Big Data Res Hlth Inst Biophys Key Lab RNA Biol Beijing 100101 Peoples R China Shenzhen Inst Nucl Acid Drug Res Shenzhen Bay Lab Pingshan Translat Med Ctr Shenzhen 510800 Peoples R China Chinese Acad Sci Inst Comp Technol Beijing Peoples R China

Recent advances in RNA engineering have enabled the development of RNA-based therapeutics for a broad spectrum of applications. Developing RNA therapeutics start with targeted RNA screening and move to the drug design and optimization. However, existing target screening tools ignore noncoding RNAs and their disease-relevant regulatory relationships. And designing therapeutic RNAs encounters high computational complexity of multi-objective optimization to overcome the immunogenicity, insta-bility and inefficient translational production. To unlock the therapeutic potential of noncoding RNAs and enable one-stop screening and design of therapeutic RNAs, we have built the platform TREAT. It incorpo-rates 43,087,953 regulatory relationships between coding and noncoding genes from 81 biological net-works under different physiological conditions. TREAT introduces graph representation learning with Random Walk Diffusions to perform disease-relevant target screening, in addition to the commonly uti-lized Topological Degree and PageRank algorithms. Design and optimization of large RNAs or interfering RNAs are both available. To reduce the computational complexity of multi-objective optimization for large RNA, we stratified the features into local and global features. The local features are evaluated on the fixed-length or dynamic-length local bins, whereas the latter are inspired by AI language models of protein sequence. Then the global assessment is performed on refined candidates, thus reducing the enormous search space. Overall, TREAT is a one-stop platform for the screening and designing of thera-peutic RNAs, with particular attention to noncoding RNAs and cutting-edge AI technology embedded, leading the progress of innovative therapeutics for challenging diseases. TREAT is freely accessible at https://***/treat.(c) 2022 The Authors. Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology. This is an open access artic

关键词： RNA Therapeutics noncoding

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Current trends in drug metabolism and pharmacokinetics

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Acta Pharmaceutica Sinica B 2019年第6期9卷 1113-1144页

作者： Yuhua Li Qiang Meng Mengbi Yang Dongyang Liu Xiangyu Hou Lan Tang Xin Wang Yuanfeng Lyu Xiaoyan Chen Kexin Liu Ai-Ming Yu Zhong Zuo Huichang Bi School of Pharmaceutical Sciences Sun Yat-sen UniversityGuangzhou 510275China The First Affiliated Hospital of Nanchang University Nanchang 330006China College of Pharmacy Dalian Medical UniversityDalian 116044China School of Pharmacy the Chinese University of Hong KongHong KongChina Drug Clinical Trial Center Peking University Third HospitalBeijing 100191China Shanghai Institute of Materia Medica Chinese Academy of SciencesShanghai 201203China School of Pharmaceutical Sciences Southern Medical UniversityGuangzhou 510515China School of Life Sciences East China Normal UniversityShanghai 200241China UC Davis School of Medicine SacramentoCA 95817USA

Pharmacokinetics(PK)is the study of the absorption,distribution,metabolism,and excretion(ADME)processes of a *** PK properties is essential for drug development and precision *** this review we provided an overview of recent research on PK with focus on the following aspects:(1)an update on drug-metabolizing enzymes and transporters in the determination of PK,as well as advances in xenobiotic receptors and noncoding RNAs(ncRNAs)in the modulation of PK,providing new understanding of the transcriptional and posttranscriptional regulatory mechanisms that result in inter-individual variations in pharmacotherapy;(2)current status and trends in assessing drug-drug interactions,especially interactions between drugs and herbs,between drugs and therapeutic biologies,and microbiota-mediated interactions:(3)advances in understanding the effects of diseases on PK,particularly changes in metabolizing enzymes and transporters with disease progression;(4)trends in mathematical modeling including physiologically-based PK modeling and novel animal models such as CRISPR/Cas9-based animal models for DMPK studies:(5)emerging non-classical xenobiotic metabolic pathways and the involvement of novel metabolic enzymes,especially *** challenges and perspectives on future directions are discussed,and may stimulate the development of new research models,technologies,and strategies towards the development of better drugs and improved clinical practice.

关键词： Pharmacokinetics Drug metabolism Drug-drug interactions Modeling Metabolizing enzymes Transporters Nuclear receptors noncoding RNAs

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Recognition of unknown conserved alternatively spliced exons

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PLOS COMPUTATIONAL BIOLOGY 2005年第2期1卷 113-122页

作者： Ohler, U Shomron, N Burge, CB MIT Dept Biol Cambridge MA 02139 USA

The split structure of most mammalian protein-coding genes allows for the potential to produce multiple different mRNA and protein isoforms from a single gene locus through the process of alternative splicing (AS). We propose a computational approach called UNCOVER based on a pair hidden Markov model to discover conserved coding exonic sequences subject to AS that have so far gone undetected. Applying UNCOVER to orthologous introns of known human and mouse genes predicts skipped exons or retained introns present in both species, while discriminating them from conserved noncoding sequences. The accuracy of the model is evaluated on a curated set of genes with known conserved AS events. The prediction of skipped exons in the similar to 1% of the human genome represented by the ENCODE regions leads to more than 50 new exon candidates. Five novel predicted AS exons were validated by RT-PCR and sequencing analysis of 15 introns with strong UNCOVER predictions and lacking EST evidence. These results imply that a considerable number of conserved exonic sequences and associated isoforms are still completely missing from the current annotation of known genes. UNCOVER also identifies a small number of candidates for conserved intron retention.

关键词： .pair introns noncoding alternative splicing Exons Markov model UNCOVER

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Novel and stress-regulated microRNAs and other small RNAs from Arabidopsis

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PLANT CELL 2004年第8期16卷 2001-2019页

作者： Sunkar, R Zhu, JK Univ Calif Riverside Inst Integrat Genome Biol Riverside CA 92521 USA Univ Calif Riverside Dept Bot & Plant Sci Riverside CA 92521 USA

MicroRNAs (miRNAs) and short interfering RNAs (siRNAs) are small noncoding RNAs that have recently emerged as important regulators of mRNA degradation, translational repression, and chromatin modification. In Arabidopsis thaliana, 43 miRNAs comprising 15 families have been reported thus far. In an attempt to identify novel and abiotic stress regulated miRNAs and siRNAs, we constructed a library of small RNAs from Arabidopsis seedlings exposed to dehydration, salinity, or cold stress or to the plant stress hormone abscisic acid. Sequencing of the library and subsequent analysis revealed 26 new miRNAs from 34 loci, forming 15 new families. Two of the new miRNAs from three loci are members of previously reported miR171 and miR319 families. Some of the miRNAs are preferentially expressed in specific tissues, and several are either upregulated or downregulated by abiotic stresses. Ten of the miRNAs are highly conserved in other plant species. Fifty-one potential targets with diverse function were predicted for the newly identified miRNAs based on sequence complementarity. In addition to miRNAs, we identified 102 other novel endogenous small RNAs in Arabidopsis. These findings suggest that a large number of miRNAs and other small regulatory RNAs are encoded by the Arabidopsis genome and that some of them may play important roles in plant responses to environmental stresses as well as in development and genome maintenance.

关键词： .dehydration siRNAs seedlings noncoding Small RNAs abiotic stresses translational repression new families Jian-Kang new miRNAs

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The evolution of word composition in metazoan promoter sequence

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PLOS COMPUTATIONAL BIOLOGY 2006年第11期2卷 1343-1348页

作者： Bush, Eliot C. Lahn, Bruce T. Univ Chicago Dept Human Genet Chicago IL 60637 USA Univ Chicago Howard Hughes Med Inst Chicago IL 60637 USA

The field of molecular evolution provides many examples of the principle that molecular differences between species contain information about evolutionary history. One surprising case can be found in the frequency of short words in DNA: more closely related species have more similar word compositions. Interest in this has often focused on its utility in deducing phylogenetic relationships. However, it is also of interest because of the opportunity it provides for studying the evolution of genome function. Word-frequency differences between species change too slowly to be purely the result of random mutational drift. Rather, their slow pattern of change reflects the direct or indirect action of purifying selection and the presence of functional constraints. Many such constraints are likely to exist, and an important challenge is to distinguish them. Here we develop a method to do so by isolating the effects acting at different word sizes. We apply our method to 2- ,4-, and 8-base-pair (bp) words across several classes of noncoding sequence. Our major result is that similarities in 8-bp word frequencies scale with evolutionary time for regions immediately upstream of genes. This association is present although weaker in intronic sequence, but cannot be detected in intergenic sequence using our method. In contrast, 2-bp and 4-bp word frequencies scale with time in all classes of noncoding sequence. These results suggest that different genomic processes are involved at different word sizes. The pattern in 2-bp and 4-bp words may be due to evolutionary changes in processes such as DNA replication and repair, as has been suggested before. The pattern in 8-bp words may reflect evolutionary changes in generegulatory machinery, such as changes in the frequencies of transcription-factor binding sites, or in the affinity of transcription factors for particular sequences.

关键词： .intergenic Sizes Intronic closely related purifying noncoding evolutionary time metazoan word-frequency Evolution of Word short words different word bp words word frequencies

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Expression signatures of long non-coding RNA and mRNA in human traumatic brain injury

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Neural Regeneration Research 2019年第4期14卷 632-641页

作者： Li-Xiang Yang Li-Kun Yang Jie Zhu Jun-Hui Chen Yu-Hai Wang Kun Xiong Department of Neurosurgery 101st Hospital of People's Liberation Army Department of Anatomy and Neurobiology School of Basic Medical Sciences Central South University

Long non-coding RNAs(lncRNAs) play a key role in craniocerebral disease, although their expression profiles in human traumatic brain injury are still unclear. In this regard, in this study, we examined brain injury tissue from three patients of the 101 st Hospital of the People's Liberation Army, China(specifically, a 36-year-old male, a 52-year-old female, and a 49-year-old female), who were diagnosed with traumatic brain injury and underwent brain contusion removal surgery. Tissue surrounding the brain contusion in the three patients was used as control tissue to observe expression characteristics of lncRNAs and mRNAs in human traumatic brain injury tissue. Volcano plot filtering identified 99 lncRNAs and 63 mRNAs differentially expressed in frontotemporal tissue of the two groups(P < 0.05, fold change > 1.2). Microarray analysis showed that 43 lncRNAs were up-regulated and 56 lncRNAs were down-regulated. Meanwhile, 59 mRNAs were up-regulated and 4 mRNAs were down-regulated. Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) analyses revealed 27 signaling pathways associated with target genes and, in particular, legionellosis and influenza A signaling pathways. Subsequently, a lncRNA-gene network was generated, which showed an absolute correlation coefficient value > 0.99 for 12 lncRNA-mRNA pairs. Finally, quantitative real-time polymerase chain reaction confirmed different expression of the five most up-regulated mRNAs within the two groups, which was consistent with the microarray results. In summary, our results show that expression profiles of mRNAs and lncRNAs are significantly different between human traumatic brain injury tissue and surrounding tissue, providing novel insight regarding lncRNAs' involvement in human traumatic brain injury. All participants provided informed consent. This research was registered in the Chinese Clinical Trial Registry(registration number: ChiCTR-TCC-13004002) and the protocol version number is 1.0.

关键词： nerve regeneration human traumatic brain injuries long noncoding RNA messenger RNA GO analysis real-time quantitative polymerase chain reaction biomarkers microarray analysis biological processes medical informatics neural regeneration

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Regulation of flowering time and floral organ identity by a microRNA and its APETALA2-like target genes

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PLANT CELL 2003年第11期15卷 2730-2741页

作者： Aukerman, MJ Sakai, H EI DuPont Nemours & Co Newark DE 19711 USA

MicroRNAs (miRNAs) are similar to21-nucleotide noncoding RNAs that have been identified in both animals and plants. Although in animals there is direct evidence implicating particular miRNAs in the control of developmental timing, to date it is not known whether plant miRNAs also play a role in regulating temporal transitions. Through an activation-tagging approach, we demonstrate that miRNA 172 (miR172) causes early flowering and disrupts the specification of floral organ identity when overexpressed in Arabidopsis. miR172 normally is expressed in a temporal manner, consistent with its proposed role in flowering time control. The regulatory target of miR172 is a subfamily of APETALA2 (AP2) transcription factor genes. We present evidence that miR172 downregulates these target genes by a translational mechanism rather than by RNA cleavage. Gain-of-function and loss-of-function analyses indicate that two of the AP2-like target genes normally act as floral repressors, supporting the notion that miR172 regulates flowering time by downregulating AP2-like target genes.

关键词： .RNA cleavage normally noncoding microRNAs target genes regulates loss-of-function organ identity developmental timing apetala Time and Floral plant miRNAs miRNA miR AP like target floral repressors

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