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      NF90/ILF3 is a transcription factor that promotes proliferation over differentiation by hierarchical regulation in K562 erythroleukemia cells

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          Abstract

          NF90 and splice variant NF110 are DNA- and RNA-binding proteins encoded by the Interleukin enhancer-binding factor 3 ( ILF3) gene that have been established to regulate RNA splicing, stabilization and export. The roles of NF90 and NF110 in regulating transcription as chromatin-interacting proteins have not been comprehensively characterized. Here, chromatin immunoprecipitation followed by deep sequencing (ChIP-seq) identified 9,081 genomic sites specifically occupied by NF90/NF110 in K562 cells. One third of NF90/NF110 peaks occurred at promoters of annotated genes. NF90/NF110 occupancy colocalized with chromatin marks associated with active promoters and strong enhancers. Comparison with 150 ENCODE ChIP-seq experiments revealed that NF90/NF110 clustered with transcription factors exhibiting preference for promoters over enhancers ( POLR2A, MYC, YY1). Differential gene expression analysis following shRNA knockdown of NF90/NF110 in K562 cells revealed that NF90/NF110 activates transcription factors that drive growth and proliferation ( EGR1, MYC), while attenuating differentiation along the erythroid lineage ( KLF1). NF90/NF110 associates with chromatin to hierarchically regulate transcription factors that promote proliferation and suppress differentiation.

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          Most cited references52

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          RNA maps reveal new RNA classes and a possible function for pervasive transcription.

          Significant fractions of eukaryotic genomes give rise to RNA, much of which is unannotated and has reduced protein-coding potential. The genomic origins and the associations of human nuclear and cytosolic polyadenylated RNAs longer than 200 nucleotides (nt) and whole-cell RNAs less than 200 nt were investigated in this genome-wide study. Subcellular addresses for nucleotides present in detected RNAs were assigned, and their potential processing into short RNAs was investigated. Taken together, these observations suggest a novel role for some unannotated RNAs as primary transcripts for the production of short RNAs. Three potentially functional classes of RNAs have been identified, two of which are syntenically conserved and correlate with the expression state of protein-coding genes. These data support a highly interleaved organization of the human transcriptome.
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            Transcription regulation and animal diversity.

            Whole-genome sequence assemblies are now available for seven different animals, including nematode worms, mice and humans. Comparative genome analyses reveal a surprising constancy in genetic content: vertebrate genomes have only about twice the number of genes that invertebrate genomes have, and the increase is primarily due to the duplication of existing genes rather than the invention of new ones. How, then, has evolutionary diversity arisen? Emerging evidence suggests that organismal complexity arises from progressively more elaborate regulation of gene expression.
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              Large-scale meta-analysis of cancer microarray data identifies common transcriptional profiles of neoplastic transformation and progression.

              Many studies have used DNA microarrays to identify the gene expression signatures of human cancer, yet the critical features of these often unmanageably large signatures remain elusive. To address this, we developed a statistical method, comparative metaprofiling, which identifies and assesses the intersection of multiple gene expression signatures from a diverse collection of microarray data sets. We collected and analyzed 40 published cancer microarray data sets, comprising 38 million gene expression measurements from >3,700 cancer samples. From this, we characterized a common transcriptional profile that is universally activated in most cancer types relative to the normal tissues from which they arose, likely reflecting essential transcriptional features of neoplastic transformation. In addition, we characterized a transcriptional profile that is commonly activated in various types of undifferentiated cancer, suggesting common molecular mechanisms by which cancer cells progress and avoid differentiation. Finally, we validated these transcriptional profiles on independent data sets.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: SoftwareRole: Writing – original draftRole: Writing – review & editing
                Role: InvestigationRole: MethodologyRole: Writing – review & editing
                Role: Data curationRole: InvestigationRole: MethodologyRole: Project administrationRole: Resources
                Role: InvestigationRole: MethodologyRole: Resources
                Role: Data curationRole: Formal analysisRole: MethodologyRole: SoftwareRole: ValidationRole: Writing – review & editing
                Role: Funding acquisitionRole: Project administrationRole: ResourcesRole: Supervision
                Role: ConceptualizationRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: SupervisionRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                28 March 2018
                2018
                : 13
                : 3
                : e0193126
                Affiliations
                [1 ] Pulmonary and Critical Care Medicine, Stanford University School of Medicine, Stanford, California, United States of America
                [2 ] Biomedical Informatics, Stanford University School of Medicine, Stanford, California, United States of America
                [3 ] Department of Genetics, Stanford University School of Medicine, Stanford, California, United States of America
                [4 ] Stanford Center for Genomics and Personalized Medicine, Stanford University School of Medicine, Palo Alto, California, United States of America
                Yeshiva University Albert Einstein College of Medicine, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0003-2968-5456
                Article
                PONE-D-17-39381
                10.1371/journal.pone.0193126
                5873942
                29590119
                3c95e7dc-2f3a-4e9f-a1fa-b082398eace0
                © 2018 Wu et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 6 November 2017
                : 5 February 2018
                Page count
                Figures: 6, Tables: 2, Pages: 21
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/100000060, National Institute of Allergy and Infectious Diseases;
                Award ID: 1 R01 AI39624
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: U54HG006996
                Award Recipient :
                This study was supported by the National Institutes of Health; R01 AI39624 provided support for PNK and LF; and U54 HG006996 provided support for JA, MS, RVN and MPS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Cell Biology
                Chromosome Biology
                Chromatin
                Biology and Life Sciences
                Genetics
                Epigenetics
                Chromatin
                Biology and Life Sciences
                Genetics
                Gene Expression
                Chromatin
                Biology and Life Sciences
                Genetics
                Gene Expression
                Gene Regulation
                Biology and Life Sciences
                Genetics
                Gene Expression
                Gene Regulation
                Transcriptional Control
                Biology and Life Sciences
                Genetics
                Gene Expression
                Biology and life sciences
                Biochemistry
                Proteins
                DNA-binding proteins
                Transcription Factors
                Biology and Life Sciences
                Genetics
                Gene Expression
                Gene Regulation
                Transcription Factors
                Biology and Life Sciences
                Biochemistry
                Proteins
                Regulatory Proteins
                Transcription Factors
                Biology and life sciences
                Genetics
                Gene expression
                DNA transcription
                Research and Analysis Methods
                Database and Informatics Methods
                Bioinformatics
                Sequence Analysis
                Sequence Motif Analysis
                Biology and life sciences
                Computational biology
                Genome complexity
                Non-coding RNA sequences
                Biology and life sciences
                Genetics
                Genomics
                Genome complexity
                Non-coding RNA sequences
                Custom metadata
                Validation data for antibody used against NF90/NF110 (mAb DRBP76; BD 612155) have been deposited to ENCODE data portal with accession ENCAB201MQH ( https://www.encodeproject.org/experiments/ENCSR632TJQ/). ChIP-seq data have been deposited at: GEO Accession GSE103215; ArrayExpress accession E-MTAB-6042. A compilation of our NF90/NF110 ChIP-Seq data together with publically available data tracks accessed on ENCODE portal is available at the UCSC browser session: http://genome.ucsc.edu/cgi-bin/hgTracks?hgS_doOtherUser=submit&hgS_otherUserName=peterkao&hgS_otherUserSessionName=thsuanwu_ILF3ChIP_20170807.

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