%0 Journal Article %J Plant Direct %D 2019 %T Arabidopsis bioinformatics resources: The current state, challenges, and priorities for the future %A Colleen Doherty %A Joanna Friesner %A Brian Gregory %A Ann Loraine %A Molly Megraw %A Nicholas Provart %A R Keith Slotkin %A Chris Town %A Sarah M Assmann %A Michael Axtell %A Tanya Berardini %A Sixue Chen %A Malia Gehan %A Eva Huala %A Pankaj Jaiswal %A Stephen Larson %A Song Li %A Sean May %A Todd Michael %A Chris Pires %A Chris Topp %A Justin Walley %A Eve Wurtele %B Plant Direct %V 3 %8 01/2019 %G eng %U https://onlinelibrary.wiley.com/doi/full/10.1002/pld3.109 %N 1 %0 Journal Article %J BMC Bioinformatics %D 2019 %T PlantSimLab-a modeling and simulation web tool for plant biologists %A S Ha %A E Dimitrova %A Stefan Hoops %A D Altarawy %A M Ansariola %A D Deb %A J Glazebrook %A R Hillmer %A H Shahin %A F Katagiri %A J McDowell %A M Megraw %A J Setubal %A BM Tyler %A Reinhard Laubenbacher %B BMC Bioinformatics %V 20 %P 1-11 %8 12/2019 %G eng %U https://bmcbioinformatics.biomedcentral.com/articles/10.1186/s12859-019-3094-9 %N 1 %0 Journal Article %J Dev Cell %D 2016 %T Establishment of Expression in the SHORTROOT-SCARECROW Transcriptional Cascade through Opposing Activities of Both Activators and Repressors %A Sparks, E. E. %A Drapek, C. %A Gaudinier, A. %A Li, S. %A Ansariola, M. %A Shen, N. %A Hennacy, J. H. %A Zhang, J. %A Turco, G. %A Petricka, J. J. %A Foret, J. %A Hartemink, A. J. %A Gordan, R. %A Megraw, M. %A Brady, S. M. %A Benfey, P. N. %K Arabidopsis Proteins/ genetics/ metabolism %K Arabidopsis/ genetics/growth & development/ metabolism %K Computer Simulation %K Gene Expression Regulation, Plant %K Gene Regulatory Networks %K Genes, Plant %K Genes, Reporter %K Genes, Synthetic %K Models, Genetic %K Plant Roots/cytology/metabolism %K Plants, Genetically Modified %K Promoter Regions, Genetic %K Repressor Proteins/genetics/metabolism %K Trans-Activators/genetics/metabolism %K Transcription Factors/ genetics/ metabolism %K Two-Hybrid System Techniques %X

Tissue-specific gene expression is often thought to arise from spatially restricted transcriptional cascades. However, it is unclear how expression is established at the top of these cascades in the absence of pre-existing specificity. We generated a transcriptional network to explore how transcription factor expression is established in the Arabidopsis thaliana root ground tissue. Regulators of the SHORTROOT-SCARECROW transcriptional cascade were validated in planta. At the top of this cascade, we identified both activators and repressors of SHORTROOT. The aggregate spatial expression of these regulators is not sufficient to predict transcriptional specificity. Instead, modeling, transcriptional reporters, and synthetic promoters support a mechanism whereby expression at the top of the SHORTROOT-SCARECROW cascade is established through opposing activities of activators and repressors.

%B Dev Cell %V 39 %P 585-596 %8 12/2016 %@ 1878-1551 (Electronic)1534-5807 (Linking) %G eng %U https://doi.org/10.1016/j.devcel.2016.09.031 %! Developmental cell %0 Journal Article %J Plant Cell %D 2014 %T Paired-end analysis of transcription start sites in Arabidopsis reveals plant-specific promoter signatures. %A Morton, Taj %A Petricka, Jalean %A Corcoran, David L %A Li, Song %A Winter, Cara M %A Carda, Alexa %A Benfey, Philip N %A Ohler, Uwe %A Megraw, Molly %K Arabidopsis %K Arabidopsis Proteins %K Binding Sites %K Cluster Analysis %K DNA, Plant %K Gene Expression Regulation, Plant %K Genome, Plant %K Models, Genetic %K Nucleotide Motifs %K Plant Roots %K Promoter Regions, Genetic %K RNA, Messenger %K RNA, Plant %K Sequence Analysis, DNA %K Species Specificity %K TATA Box %K Transcription Factors %K Transcription Initiation Site %X

Understanding plant gene promoter architecture has long been a challenge due to the lack of relevant large-scale data sets and analysis methods. Here, we present a publicly available, large-scale transcription start site (TSS) data set in plants using a high-resolution method for analysis of 5' ends of mRNA transcripts. Our data set is produced using the paired-end analysis of transcription start sites (PEAT) protocol, providing millions of TSS locations from wild-type Columbia-0 Arabidopsis thaliana whole root samples. Using this data set, we grouped TSS reads into "TSS tag clusters" and categorized clusters into three spatial initiation patterns: narrow peak, broad with peak, and weak peak. We then designed a machine learning model that predicts the presence of TSS tag clusters with outstanding sensitivity and specificity for all three initiation patterns. We used this model to analyze the transcription factor binding site content of promoters exhibiting these initiation patterns. In contrast to the canonical notions of TATA-containing and more broad "TATA-less" promoters, the model shows that, in plants, the vast majority of transcription start sites are TATA free and are defined by a large compendium of known DNA sequence binding elements. We present results on the usage of these elements and provide our Plant PEAT Peaks (3PEAT) model that predicts the presence of TSSs directly from sequence.

[Link to Additional Data and Supplementary Materials]

%B Plant Cell %V 26 %P 2746-60 %8 2014 Jul %G eng %N 7 %R 10.1105/tpc.114.125617 %0 Journal Article %J Mol Syst Biol %D 2011 %T A stele-enriched gene regulatory network in the Arabidopsis root. %A Brady, Siobhan M %A Zhang, Lifang %A Megraw, Molly %A Martinez, Natalia J %A Jiang, Eric %A Yi, Charles S %A Liu, Weilin %A Zeng, Anna %A Taylor-Teeples, Mallorie %A Kim, Dahae %A Ahnert, Sebastian %A Ohler, Uwe %A Ware, Doreen %A Walhout, Albertha J M %A Benfey, Philip N %K Arabidopsis %K Arabidopsis Proteins %K Gene Expression Profiling %K Gene Regulatory Networks %K MicroRNAs %K Plant Roots %K Reproducibility of Results %K Systems Biology %K Transcription Factors %K Two-Hybrid System Techniques %X

Tightly controlled gene expression is a hallmark of multicellular development and is accomplished by transcription factors (TFs) and microRNAs (miRNAs). Although many studies have focused on identifying downstream targets of these molecules, less is known about the factors that regulate their differential expression. We used data from high spatial resolution gene expression experiments and yeast one-hybrid (Y1H) and two-hybrid (Y2H) assays to delineate a subset of interactions occurring within a gene regulatory network (GRN) that determines tissue-specific TF and miRNA expression in plants. We find that upstream TFs are expressed in more diverse cell types than their targets and that promoters that are bound by a relatively large number of TFs correspond to key developmental regulators. The regulatory consequence of many TFs for their target was experimentally determined using genetic analysis. Remarkably, molecular phenotypes were identified for 65% of the TFs, but morphological phenotypes were associated with only 16%. This indicates that the GRN is robust, and that gene expression changes may be canalized or buffered.

%B Mol Syst Biol %V 7 %P 459 %8 2011 Jan 18 %G eng %R 10.1038/msb.2010.114 %0 Journal Article %J J Biol Chem %D 2010 %T Editing of Epstein-Barr virus-encoded BART6 microRNAs controls their dicer targeting and consequently affects viral latency. %A Iizasa, Hisashi %A Wulff, Bjorn-Erik %A Alla, Nageswara R %A Maragkakis, Manolis %A Megraw, Molly %A Hatzigeorgiou, Artemis %A Iwakiri, Dai %A Takada, Kenzo %A Wiedmer, Andreas %A Showe, Louise %A Lieberman, Paul %A Nishikura, Kazuko %K Cell Line, Tumor %K Epstein-Barr Virus Infections %K Epstein-Barr Virus Nuclear Antigens %K Gene Silencing %K Herpesvirus 4, Human %K Humans %K Immediate-Early Proteins %K MicroRNAs %K Ribonuclease III %K RNA Editing %K RNA, Viral %K Trans-Activators %K Viral Proteins %K Virus Latency %X

Certain primary transcripts of miRNA (pri-microRNAs) undergo RNA editing that converts adenosine to inosine. The Epstein-Barr virus (EBV) genome encodes multiple microRNA genes of its own. Here we report that primary transcripts of ebv-miR-BART6 (pri-miR-BART6) are edited in latently EBV-infected cells. Editing of wild-type pri-miR-BART6 RNAs dramatically reduced loading of miR-BART6-5p RNAs onto the microRNA-induced silencing complex. Editing of a mutation-containing pri-miR-BART6 found in Daudi Burkitt lymphoma and nasopharyngeal carcinoma C666-1 cell lines suppressed processing of miR-BART6 RNAs. Most importantly, miR-BART6-5p RNAs silence Dicer through multiple target sites located in the 3'-UTR of Dicer mRNA. The significance of miR-BART6 was further investigated in cells in various stages of latency. We found that miR-BART6-5p RNAs suppress the EBNA2 viral oncogene required for transition from immunologically less responsive type I and type II latency to the more immunoreactive type III latency as well as Zta and Rta viral proteins essential for lytic replication, revealing the regulatory function of miR-BART6 in EBV infection and latency. Mutation and A-to-I editing appear to be adaptive mechanisms that antagonize miR-BART6 activities.

%B J Biol Chem %V 285 %P 33358-70 %8 2010 Oct 22 %G eng %N 43 %R 10.1074/jbc.M110.138362 %0 Journal Article %J Proc Natl Acad Sci U S A %D 2008 %T Genomic and epigenetic alterations deregulate microRNA expression in human epithelial ovarian cancer. %A Zhang, Lin %A Volinia, Stefano %A Bonome, Tomas %A Calin, George Adrian %A Greshock, Joel %A Yang, Nuo %A Liu, Chang-Gong %A Giannakakis, Antonis %A Alexiou, Pangiotis %A Hasegawa, Kosei %A Johnstone, Cameron N %A Megraw, Molly S %A Adams, Sarah %A Lassus, Heini %A Huang, Jia %A Kaur, Sippy %A Liang, Shun %A Sethupathy, Praveen %A Leminen, Arto %A Simossis, Victor A %A Sandaltzopoulos, Raphael %A Naomoto, Yoshio %A Katsaros, Dionyssios %A Gimotty, Phyllis A %A DeMichele, Angela %A Huang, Qihong %A Bützow, Ralf %A Rustgi, Anil K %A Weber, Barbara L %A Birrer, Michael J %A Hatzigeorgiou, Artemis G %A Croce, Carlo M %A Coukos, George %K DNA, Neoplasm %K Down-Regulation %K Epigenesis, Genetic %K Epithelial Cells %K Female %K Gene Expression Profiling %K Gene Expression Regulation, Neoplastic %K Genome, Human %K Humans %K MicroRNAs %K Neoplasm Staging %K Ovarian Neoplasms %K Ribonuclease III %K RNA, Messenger %K Survival Analysis %X

MicroRNAs (miRNAs) are an abundant class of small noncoding RNAs that function as negative gene regulators. miRNA deregulation is involved in the initiation and progression of human cancer; however, the underlying mechanism and its contributions to genome-wide transcriptional changes in cancer are still largely unknown. We studied miRNA deregulation in human epithelial ovarian cancer by integrative genomic approach, including miRNA microarray (n = 106), array-based comparative genomic hybridization (n = 109), cDNA microarray (n = 76), and tissue array (n = 504). miRNA expression is markedly down-regulated in malignant transformation and tumor progression. Genomic copy number loss and epigenetic silencing, respectively, may account for the down-regulation of approximately 15% and at least approximately 36% of miRNAs in advanced ovarian tumors and miRNA down-regulation contributes to a genome-wide transcriptional deregulation. Last, eight miRNAs located in the chromosome 14 miRNA cluster (Dlk1-Gtl2 domain) were identified as potential tumor suppressor genes. Therefore, our results suggest that miRNAs may offer new biomarkers and therapeutic targets in epithelial ovarian cancer.

%B Proc Natl Acad Sci U S A %V 105 %P 7004-9 %8 2008 May 13 %G eng %N 19 %R 10.1073/pnas.0801615105 %0 Journal Article %J Proc Natl Acad Sci U S A %D 2006 %T microRNAs exhibit high frequency genomic alterations in human cancer. %A Zhang, Lin %A Huang, Jia %A Yang, Nuo %A Greshock, Joel %A Megraw, Molly S %A Giannakakis, Antonis %A Liang, Shun %A Naylor, Tara L %A Barchetti, Andrea %A Ward, Michelle R %A Yao, George %A Medina, Angelica %A O'brien-Jenkins, Ann %A Katsaros, Dionyssios %A Hatzigeorgiou, Artemis %A Gimotty, Phyllis A %A Weber, Barbara L %A Coukos, George %K Breast Neoplasms %K Female %K Gene Dosage %K Gene Expression Profiling %K Humans %K MicroRNAs %K Neoplasms %K Nucleic Acid Hybridization %K Oligonucleotide Array Sequence Analysis %K Ovarian Neoplasms %K Statistics as Topic %X

MicroRNAs (miRNAs) are endogenous noncoding RNAs, which negatively regulate gene expression. To determine genomewide miRNA DNA copy number abnormalities in cancer, 283 known human miRNA genes were analyzed by high-resolution array-based comparative genomic hybridization in 227 human ovarian cancer, breast cancer, and melanoma specimens. A high proportion of genomic loci containing miRNA genes exhibited DNA copy number alterations in ovarian cancer (37.1%), breast cancer (72.8%), and melanoma (85.9%), where copy number alterations observed in >15% tumors were considered significant for each miRNA gene. We identified 41 miRNA genes with gene copy number changes that were shared among the three cancer types (26 with gains and 15 with losses) as well as miRNA genes with copy number changes that were unique to each tumor type. Importantly, we show that miRNA copy changes correlate with miRNA expression. Finally, we identified high frequency copy number abnormalities of Dicer1, Argonaute2, and other miRNA-associated genes in breast and ovarian cancer as well as melanoma. These findings support the notion that copy number alterations of miRNAs and their regulatory genes are highly prevalent in cancer and may account partly for the frequent miRNA gene deregulation reported in several tumor types.

%B Proc Natl Acad Sci U S A %V 103 %P 9136-41 %8 2006 Jun 13 %G eng %N 24 %R 10.1073/pnas.0508889103