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MiR-200a regulates epithelial to mesenchymal transition-related gene expression and determines prognosis in colorectal cancer patients

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BRITISH JOUrnaL OF CANCER 2014年第6期110卷 1614-1621页

作者： Pichler, M. Ress, A. L. Winter, E. Stiegelbauer, V. Karbiener, M. Schwarzenbacher, D. Scheideler, M. Ivan, C. Jahn, S. W. Kiesslich, T. Gerger, A. Bauernhofer, T. Calin, G. A. Hoefler, G. Med Univ Graz MUG Dept Internal Med Div Oncol Graz Austria Univ Texas MD Anderson Canc Ctr Dept Expt Therapeut Houston TX 77030 USA Med Univ Graz MUG Inst Pathol Graz Austria Graz Univ Technol Inst Genom & Bioinformat RNA Biol Grp A-8010 Graz Austria Paracelsus Med Univ Salzburger Landeskliniken SALK Dept Internal Med 1 Salzburg Austria Paracelsus Med Univ Inst Physiol & Pathophysiol Salzburg Austria

Background: Micrornas (mirnas) regulate the biological properties of colorectal cancer (CRC) cells and might serve as potential prognostic factors and therapeutic targets. In this study, we therefore globally profiled mirnas associated with E-cadherin expression in CRC cells in an attempt to identify mirnas that are associated with aggressive clinical course in CRC patients. Methods: Two CRC cell lines (Caco-2 and HRT-18) with different E-cadherin expression pattern were profiled for differences in abundance for more than 1000 human mirnas using microarray technology. One of the most differentially expressed mirnas, miR-200a was evaluated for its prognostic role in a cohort of 111 patients and independently validated in 217 patients of the Cancer Genome Atlas data set. To further characterise the biological role of miR-200a expression in CRC, in vitro miR-200a inhibition and overexpression were performed and the effects on cellular growth, apoptosis and epithelial-mesenchymal transition (EMT)-related gene expression were explored. Results: In situ hybridisation specifically localised miR-200a in CRC cells. In both cohorts, a low miR-200a expression was associated with poor survival (P < 0.05). Multivariate Cox regression analysis identified low levels of miR-200a expression as an independent prognostic factor with respect to cancer-specific survival (HR =2.04, CI =1.28-3.25, P < 0.002). Gain and loss of function assays for miR-200a in vitro led to a significantly differential and converse expression of EMT-related genes ( P < 0.001.) A low expression of miR-200a was also observed in cancer stem cell-enriched spheroid growth conditions (P < 0.05). Conclusions: In conclusion, our data suggest that low miR-200a expression is associated with poor prognosis in CRC patients. MiR-200a has a regulatory effect on EMT and is associated with cancer stem cell properties in CRC.

关键词： colorectal cancer non-coding rna microrna prognosis

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Characterisation of novel micrornas in the Black flying fox (Pteropus alecto) by deep sequencing

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BMC GENOMICS 2014年第1期15卷 1-13页

作者： Cowled, Christopher Stewart, Cameron R. Likic, Vladimir A. Friedlaender, Marc R. Tachedjian, Mary Jenkins, Kristie A. Tizard, Mark L. Cottee, Pauline Marsh, Glenn A. Zhou, Peng Baker, Michelle L. Bean, Andrew G. Wang, Lin-fa CSIRO Australian Anim Hlth Lab Geelong Vic 3220 Australia Bio21 Mol Sci & Biotechnol Inst Melbourne Australia Ctr Genom Regulat CRG Barcelona Spain Univ Pompeu Fabra UPF Barcelona Spain Duke NUS Grad Med Sch Program Emerging Infect Dis Singapore 169857 Singapore

Background: Bats are a major source of new and emerging viral diseases. Despite the fact that bats carry and shed highly pathogenic viruses including Ebola, Nipah and SARS, they rarely display clinical symptoms of infection. Host factors influencing viral replication are poorly understood in bats and are likely to include both pre- and post-transcriptional regulatory mechanisms. Micrornas are a major mechanism of post-transcriptional gene regulation, however very little is known about them in bats. Results: This study describes 399 micrornas identified by deep sequencing of small rna isolated from tissues of the Black flying fox, Pteropus alecto, a confirmed natural reservoir of the human pathogens Hendra virus and Australian bat lyssavirus. Of the micrornas identified, more than 100 are unique amongst vertebrates, including a subset containing mutations in critical seed regions. Clusters of rapidly-evolving micrornas were identified, as well as micrornas predicted to target genes involved in antiviral immunity, the DNA damage response, apoptosis and autophagy. Closer inspection of the predicted targets for several highly supported novel mirna candidates suggests putative roles in host-virus interaction. Conclusions: Micrornas are likely to play major roles in regulating virus-host interaction in bats, via dampening of inflammatory responses (limiting the effects of immunopathology), and directly limiting the extent of viral replication, either through restricting the availability of essential factors or by controlling apoptosis. Characterisation of the bat microrna repertoire is an essential step towards understanding transcriptional regulation during viral infection, and will assist in the identification of mechanisms that enable bats to act as natural virus reservoirs. This in turn will facilitate the development of antiviral strategies for use in humans and other species.

关键词： Bats Chiroptera Pteropus alecto Microrna non-coding rna Transcriptome

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Oligonucleotide Analogues as Modulators of the Expression and Function of noncoding rnas (ncrnas): Emerging Therapeutics Applications

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JOUrnaL OF MEDICINAL CHEMISTRY 2014年第24期57卷 10220-10240页

作者： Avitabile, Concetta Cimmino, Amelia Romanelli, Alessandra Univ Naples Federico II Dipartimento Farm I-80134 Naples Italy CNR Ist Genet & Biofis Adriano Buzzati Traverso I-80131 Naples Italy Ist Ricovero & Cura Carattere Sci SDN IRCC I-80142 Naples Italy

ncrnas are emerging as key regulators of physiological and pathological processes and therefore have been identified as pharmacological targets and as markers for some diseases. Oligonucleotide analogues represent so far the most widely employed tool for the modulation of the expression of ncrnas. In this perspective we briefly describe most of the known classes of ncrnas and then we discuss the design and the applications of oligonucleotide analogues for their targeting. The effects of modifications of the chemical structure of the oligonucleotides on properties such as the binding affinity toward targets and off targets, and the stability to degradation and their biological effects (when known) are discussed. Examples of molecules currently used in clinical trials are also reported.

关键词： OLIGONUCLEOTIDES GENE expression non-coding rna CHEMICAL structure DRUG targeting

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The Long noncoding rnas NEAT1 and MALAT1 Bind Active Chromatin Sites

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MOLECULAR CELL 2014年第5期55卷 791-802页

作者： West, Jason A. Davis, Christopher P. Sunwoo, Hongjae Simon, Matthew D. Sadreyev, Ruslan I. Wang, Peggy I. Tolstorukov, Michael Y. Kingston, Robert E. Massachusetts Gen Hosp Dept Mol Biol Boston MA 02114 USA Harvard Univ Sch Med Dept Genet Boston MA 02115 USA Massachusetts Gen Hosp Dept Pathol Boston MA 02114 USA Harvard Univ Sch Med Boston MA 02114 USA

Mechanistic roles for many lncrnas are poorly understood, in part because their direct interactions with genomic loci and proteins are difficult to assess. Using a method to purify endogenous rnas and their associated factors, we mapped the genomic binding sites for two highly expressed human lncrnas, NEAT1 and MALAT1. We show that NEAT1 and MALAT1 localize to hundreds of genomic sites in human cells, primarily over active genes. NEAT1 and MALAT1 exhibit colocalization to many of these loci, but display distinct gene body binding patterns at these sites, suggesting independent but complementary functions for these rnas. We also identified numerous proteins enriched by both lncrnas, supporting complementary binding and function, in addition to unique associated proteins. Transcriptional inhibition or stimulation alters localization of NEAT1 on active chromatin sites, implying that underlying DNA sequence does not target NEAT1 to chromatin, and that localization responds to cues involved in the transcription process.

关键词： non-coding rna BINDING sites (Biochemistry) CHROMATIN GENE expression GENETIC transcription regulation DNA sequencing

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Restitution of gene expression and histone acetylation signatures altered by hepatitis B virus through antiviral microrna-like molecules in nontransformed murine hepatocytes

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CLINICAL EPIGENETICS 2014年第1期6卷 1-15页

作者： Jenke, Andreas C. W. Hensel, Kai O. Klein, Andreas Willuhn, Lisa Prax, Susanna Weil, Patrick P. Winkler, Theodor Deba, Timo Orth, Valerie Baiker, Armin Wirth, Stefan Postberg, Jan Univ Witten Herdecke Ctr Biomed Educ & Res ZBAF Fac HlthDept Paediat Ctr Clin & Translat Res CCTRHELIOS Med Ctr Wuppe D-42283 Wuppertal Germany Bavarian Hlth & Food Safety Author D-85764 Oberschleissheim Germany

Background: Virus-host interactions result in altered gene expression profiles in host cell nuclei and enable virus particle production, thus obligatorily involving changes in their epigenomes. Neither such epigenome changes nor their response to antiviral treatment have been extensively studied to date, although viral infections are known to contribute to the long-term development of severe secondary diseases, for example, hepatocellular carcinoma. This may be causally linked to virus-induced persistent plastic chromatin deformations. Results: We studied whether impaired hepatitis B virus (HBV) replication can lead to the restitution of epigenome signatures hypothesizing that hepatocytes alternatively could adopt a 'memory' state of the infection;that is, the chromatin could persist in a HBV-induced configuration potentially inheritable between dividing hepatocytes. We therefore determined epigenomic signatures and gene expression changes altered by HBV and the effects of suppressed HBV replication in nontransformed hepatocytes of newborn mice. Further we investigated differential histone acetyltransferase and histone deacetylase activities in HBV-negative and HBVpositive hepatocytes, as well as the effects of HBV suppression on gene expression and the chromatin landscape. We show that the expression of several genes and the chromatin landscape become altered upon HBV infection, including global hypoacetylation of H2A.Z and H3K9. Reporter assays monitoring the activities of histone acetyltransferases or histone deacetylases, respectively, suggest that hypoacetylation most probably depends on elevated sirtuin deacetylase activity, but not on class I/II histone deacetylases. Using Micrococcus nuclease to study the chromatin accessibility in met murine-D3 and hepatitis B virus met murine hepatocytes, we demonstrate that the observed differences in H2A.Z/H3K9 acetylation lead to global chromatin structure changes. At all selected sites examined by chromatin immunopreci

关键词： histone deacetylation sirtuins CpG signaling non-coding rna HBV HCC

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Mammary-Specific Gene Activation Is Defined by Progressive Recruitment of STAT5 during Pregnancy and the Establishment of H3K4me3 Marks

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MOLECULAR AND CELLULAR BIOLOGY 2014年第3期34卷 464-473页

作者： Kang, Keunsoo Yamaji, Daisuke Yoo, Kyung Hyun Robinson, Gertraud W. Hennighausen, Lothar NIDDK Lab Genet & Physiol NIH Bethesda MD 20892 USA

Differentiation of mammary secretory epithelium during pregnancy is characterized by sequential activation of genes over several orders of magnitude. Although the transcription factor STAT5 is key to alveolar development, it is not clear to what extent it controls temporal activation of genetic programs in secretory epithelium. To uncover molecular mechanisms effecting progressive differentiation, we explored genome-wide STAT5 binding and H3K4me3 (i.e., trimethylated histone H3 at K4) marks in mammary tissues at early and midpregnancy and at parturition. STAT5 binding to genes induced during pregnancy was low in immature mammary tissue but increased with epithelial differentiation. Increased STAT5 binding was associated with the establishment of H3K4me3 marks and transcriptional activation. STAT5 binding preceded the formation of H3K4me3 marks in some mammary-specific genes. De novo STAT5 binding was also found at distal sites, indicating enhancers. Furthermore, we established an exhaustive mammary transcriptome. Through integration of rna-seq and STAT5 and H3K4me4 ChIP-seq data, we discovered novel mammary-specific alternative promoters and genes, including noncoding rnas. Our findings suggest that STAT5 is an early step in establishing transcription complexes on genes specifically expressed in mammary epithelium. This is the first study in an organ that links progressive chromatin occupancy of STAT5 to the acquisition of H3K4me3 marks and transcription during hormone-induced differentiation.

关键词： GENES RESEARCH CELLS IMMUNE system CYTOKINES TRANSCRIPTION factors non-coding rna HORMONES

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Global signatures of protein binding on structured rnas in Saccharomyces cerevisiae

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Science China(Life Sciences) 2014年第1期57卷 22-35页

作者： YANG YuCheng UMETSU Jumpei LU Zhi John MOE Key Lab of Bioinformatics School of Life Sciences Tsinghua University Department of Biological Information Tokyo Institute of TechnologyTokyo 152-8850 Japan

Protein binding is essential to the transport,decay and regulation of almost all rna ***,the structural preference of protein binding on rnas and their cellular functions and dynamics upon changing environmental conditions are poorly ***,we integrated various high-throughput data and introduced a computational framework to describe the global interactions between rna binding proteins(RBPs)and structured rnas in yeast at single-nucleotide *** found that on average,in terms of percent total lengths,~15%of mrna untranslated regions(UTRs),~37%of canonical non-coding rnas(ncrnas)and^11%of long ncrnas(lncrnas)are bound by *** RBP binding sites,in general,tend to occur at single-stranded loops,with evolutionarily conserved signatures,and often facilitate a specific rna structure conformation in *** found that four nucleotide modifications of trna are significantly associated with RBP *** also identified various structural motifs bound by RBPs in the UTRs of mrnas,associated with localization,degradation and stress ***,we identified>200 novel lncrnas bound by RBPs,and about half of them contain conserved secondary *** present the first ensemble pattern of RBP binding sites in the structured non-coding regions of a eukaryotic genome,emphasizing their structural context and cellular functions.

关键词： rna binding protein non-coding rna UTR rna structure Saccharomyces cerevisiae

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PREPARING THE NEXT GENERATION OF ACADEMIC CHIEF NURSE ADMINISTRATORS

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JOUrnaL OF PROFESSIONAL NURSING 2014年第4期30卷 279-280页

作者： Morton, Patricia Gonce Univ Utah Salt Lake City UT 84112 USA

The non-coding rna (ncrna) elements in the 3′ Untranslated Regions (3′-UTRs) are known to participate in the genes' post-transcriptional regulations. Inferring co-expression patterns of the genes through clustering these 3′-UTR ncrna elements will provide invaluable insights for studying their biological functions. In this paper, we propose an improved rna structural clustering pipeline. Benchmark of the new pipeline on Rfam data demonstrates over 10% performance improvements compared to the traditional hierarchical clustering pipeline. By applying the new clustering pipeline to 3′-UTRs of Drosophila melanogaster's genome, we have successfully identified 184 ncrna clusters with 91.3% accuracy. One of these clusters corresponds to genes that are preferentially expressed in male Drosophila. Another cluster contains genes that are responsible for the functions of septate junction in epithelial cells. These discoveries encourage more studies on novel post-transcriptional regulation mechanisms.

关键词： 3′ untranslated region Bioinformatics Clustering Drosophila genome non-coding rna Post-transcriptional regulation rna secondary structure Nurse Administrators septate junction Untranslated rna pipeline Post-Transcriptional Regulation Cluster Analysis Bioinformatics

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Mammalian Epigenetic Mechanisms

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IUBMB LIFE 2014年第4期66卷 240-256页

作者： Zhang, Guoqiang Pradhan, Sriharsa New England Biolabs Inc Ipswich MA USA

The mammalian genome is packaged into chromatin that is further compacted into three-dimensional structures consisting of distinct functional domains. The higher order structure of chromatin is in part dictated by enzymatic DNA methylation and histone modifications to establish epigenetic layers controlling gene expression and cellular functions, without altering the underlying DNA sequences. Apart from DNA and histone modifications, non-coding rnas can also regulate the dynamics of the mammalian gene expression and various physiological functions including cell division, differentiation, and apoptosis. Aberrant epigenetic signatures are associated with abnormal developmental processes and diseases such as cancer. In this review, we will discuss the different layers of epigenetic regulation, including writer enzymes for DNA methylation, histone modifications, non-coding rna, and chromatin conformation. We will highlight the combinatorial role of these structural and chemical modifications along with their partners in various cellular processes in mammalian cells. We will also address the cis and trans interacting reader proteins that recognize these modifications and eraser enzymes that remove these marks. Furthermore, an attempt will be made to discuss the interplay between various epigenetic writers, readers, and erasures in the establishment of mammalian epigenetic mechanisms. (c) 2014 IUBMB Life, 66(4):240-256, 2014

关键词： epigenetics DNA methylation histone modification non-coding rna chromatin conformation

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miR-888 is an expressed prostatic secretions-derived microrna that promotes prostate cell growth and migration

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CELL CYCLE 2014年第2期13卷 227-239页

作者： Lewis, Holly Lance, Raymond Troyer, Dean Beydoun, Hind Hadley, Melissa Orians, Joseph Benzine, Tiffany Madric, Kenya Semmes, O. John Drake, Richard Esquela-Kerscher, Aurora Eastern Virginia Med Sch Dept Microbiol & Mol Cell Biol Leroy T Canoles Jr Canc Res Ctr Norfolk VA 23501 USA Eastern Virginia Med Sch Dept Urol Norfolk VA 23501 USA Urol Virginia Norfolk VA USA Eastern Virginia Med Sch Grad Program Publ Hlth Norfolk VA 23501 USA

micrornas (mirnas) are a growing class of small non-coding rnas that exhibit widespread dysregulation in prostate cancer. We profiled mirna expression in syngeneic human prostate cancer cell lines that differed in their metastatic potential in order to determine their role in aggressive prostate cancer. miR-888 was the most differentially expressed mirna observed in human metastatic PC3-ML cells relative to non-invasive PC3-N cells, and its levels were higher in primary prostate tumors from cancer patients, particularly those with seminal vesicle invasion. We also examined a novel mirna-based biomarker source called expressed prostatic secretions in urine (EPS urine) for miR-888 expression and found that its levels were preferentially elevated in prostate cancer patients with high-grade disease. These expression studies indicated a correlation for miR-888 in disease progression. We next tested how miR-888 regulated cancer-related pathways in vitro using human prostate cancer cell lines. Overexpression of miR-888 increased proliferation and migration, and conversely inhibition of miR-888 activity blocked these processes. miR-888 also increased colony formation in PC3-N and LNCaP cells, supporting an oncogenic role for this mirna in the prostate. Our data indicates that miR-888 functions to promote prostate cancer progression and can suppress protein levels of the tumor suppressor genes RBL1 and SMAD4. This mirna holds promise as a diagnostic tool using an innovative prostatic fluid source as well as a therapeutic target for aggressive prostate cancer.

关键词： non-coding rna microrna mirna miR-888 prostate prostate cancer expressed prostatic secretions urine EPS urine

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