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lncRNAtor: a comprehensive resource for functional investigation of long non-coding RNAs
Park, Charny,Yu, Namhee,Choi, Ikjung,Kim, Wankyu,Lee, Sanghyuk Oxford University Press 2014 Bioinformatics Vol.30 No.17
<P><B>Motivation:</B> A number of long non-coding RNAs (lncRNAs) have been identified by deep sequencing methods, but their molecular and cellular functions are known only for a limited number of lncRNAs. Current databases on lncRNAs are mostly for cataloging purpose without providing in-depth information required to infer functions. A comprehensive resource on lncRNA function is an immediate need.</P><P><B>Results:</B> We present a database for functional investigation of lncRNAs that encompasses annotation, sequence analysis, gene expression, protein binding and phylogenetic conservation. We have compiled lncRNAs for six species (human, mouse, zebrafish, fruit fly, worm and yeast) from ENSEMBL, HGNC, MGI and lncRNAdb. Each lncRNA was analyzed for coding potential and phylogenetic conservation in different lineages. Gene expression data of 208 RNA-Seq studies (4995 samples), collected from GEO, ENCODE, modENCODE and TCGA databases, were used to provide expression profiles in various tissues, diseases and developmental stages. Importantly, we analyzed RNA-Seq data to identify coexpressed mRNAs that would provide ample insights on lncRNA functions. The resulting gene list can be subject to enrichment analysis such as Gene Ontology or KEGG pathways. Furthermore, we compiled protein–lncRNA interactions by collecting and analyzing publicly available CLIP-seq or PAR-CLIP sequencing data. Finally, we explored evolutionarily conserved lncRNAs with correlated expression between human and six other organisms to identify functional lncRNAs. The whole contents are provided in a user-friendly web interface.</P><P><B>Availability and implementation:</B> lncRNAtor is available at http://lncrnator.ewha.ac.kr/.</P><P><B>Contact:</B> sanghyuk@ewha.ac.kr</P><P><B>Supplementary information:</B> Supplementary data are available at <I>Bioinformatics</I> online.</P>
Park, Charny,Yoon, Kyong‐,Ah,Kim, Jihyun,Park, In Hae,Park, Soo Jin,Kim, Min Kyeong,Jang, Wooyeong,Cho, Soo Young,Park, Boyoung,Kong, Sun‐,Young,Lee, Eun Sook John Wiley and Sons Inc. 2019 Cancer Science Vol.110 No.5
<P>Very young breast cancer patients are more common in Asian countries than Western countries and are thought to have worse prognosis than older patients. The aim of the current study was to identify molecular characteristics of young patients with estrogen receptor (ER)‐positive breast cancer by analyzing mutations and copy number variants (CNV), and by applying expression profiling. The whole exome and transcriptome of 47 Korean young breast cancer (KYBR) patients (age <35) were analyzed. Genomic profiles were constructed using mutations, CNV and differential gene expression from sequencing data. Pathway analyses were also performed using gene sets to identify biological processes. Our data were compared with young ER+ breast cancer patients in The Cancer Genome Atlas (TCGA) dataset. <I>TP53</I>,<I>PIK3CA</I> and <I>GATA3</I> were highly recurrent somatic mutation genes. APOBEC‐associated mutation signature was more frequent in KYBR compared with young TCGA patients. Integrative profiling was used to classify our patients into 3 subgroups based on molecular characteristics. Group A showed luminal A‐like subtype and IGF1R signal dysregulation. Luminal B patients were classified into groups B and C, which showed chromosomal instability and enrichment for APOBEC3A/B deletions, respectively. Group B was characterized by 11q13 (CCND1) amplification and activation of the ubiquitin‐mediated proteolysis pathway. Group C showed 17q12 (ERBB2) amplification and lower ER and progesterone receptor expression. Group C was also distinguished by immune activation and lower epithelial‐mesenchyme transition (EMT) degree compared with group B. This study showed that integrative genomic profiling could classify very young patients with breast cancer into molecular subgroups that are potentially linked to different clinical characteristics.</P>
Host immune response index in gastric cancer identified by comprehensive analyses of tumor immunity
Park, Charny,Cho, Junhun,Lee, Jeeyun,Kang, So Young,An, Ji Yeong,Choi, Min Gew,Lee, Jun Ho,Sohn, Tae Sung,Bae, Jae Moon,Kim, Sung,Kim, Seung Tae,Park, Se Hoon,Park, Joon Oh,Kang, Won Ki,Sohn, Insuk,Ju Informa UK (Taylor Francis) 2017 Oncoimmunology Vol.6 No.11
<P>Tumor infiltrating lymphocytes (TIL) in Epstein-Barr virus (EBV)-associated/microsatellite-unstable (MSI) gastric carcinomas (GC) constitute immune-active principal cellular components of tumor microenvironment and contribute to better prognosis. With the remarkable success of cancer immunotherapies, there is an urgent need for a comprehensive understanding of tumor-immune interactions in patients with GC in the context of host immune response. To identify GC subtype-specific immune response gene set, we tested differentially expressed genes for MSI and EBV+ GC subtypes in randomly selected test set (n = 278) in merged ACRG-SMC microarray and TCGA RNA sequencing data set. We identified Host ImmunE Response index (HIERI) consisting of 29 immune genes classifying GC patients into robust 3 groups with prognostic significance. Immune-high cluster 1 was enriched with PD-L1(High)/EBV+/MSI/TILHigh with the best clinical outcome while immune-low cluster 3 displayed worst outcome and exemplified with PD-L1(Low)/EBV-/MSS. The results were validated in the same cohort (n = 279) and independent cohort (n = 181) with RNA from formalin-fixed paraffin-embedded (FFPE) tissue. Unexpectedly, nearly half of GC in cluster 1 were EBV-/MSS and 10% of cluster 3 GC were EBV+/MSI GC patients, suggesting that in addition to EBV+/MSI GC subtypes, EBV-/MSS subtype also constitutes almost half of high immune cluster and would be a good candidate for immune checkpoint inhibitor therapy. In contrary, almost 10% of EBV+/MSI GC patients may not respond to immune checkpoint inhibitor therapy. Thus, our HIERI gene signature demonstrates the potential to subclassify tumor immunity levels, predict prognosis and help immunotherapeutic decisions.</P>
Isolation and Functional Examination of the Long Non-Coding RNA Redrum
Lee, Yerim,Park, Charny,Lee, Sanghyuk,Lee, Daekee,Kim, Jaesang Korean Society for Molecular and Cellular Biology 2018 Molecules and cells Vol.41 No.2
Here, we report isolation of multiple long non-coding RNAs (lncRNAs) expressed tissue-specifically during murine embryogenesis. One of these, subsequently came to be known as Redrum, is expressed in erythropoietic cells in fetal liver and adult bone marrow. Redrum transcription is also detected during pregnancy in the spleen where extramedullary hematopoiesis takes place. In order to examine the function of Redrum in vivo, we generated a gene-targeted murine model and analyzed its embryonic and adult erythropoiesis. The homozygous mutant embryo showed no apparent deficiency or defect in erythropoiesis. Adult erythropoiesis in bone marrow and in the spleen during pregnancy likewise showed no detectable phenotype as red blood cells matured in normal fashion. The phenotype is in contrast to the reported function of Redrum in vitro, and our observation implies that Redrum plays in vivo an accessory or supplementary role whose loss is compatible with normal erythropoiesis.
Kim, Suyeon,Park, Charny,Jun, Yukyung,Lee, Sanghyuk,Jung, Yeonjoo,Kim, Jaesang Korean Society for Molecular and Cellular Biology 2018 Molecules and cells Vol.41 No.8
Mutations in spliceosome components have been implicated in carcinogenesis of various types of cancer. One of the most frequently found is U2AF1 S34F missense mutation. Functional analyses of this mutation have been largely limited to hematological malignancies although the mutation is also frequently seen in other cancer types including lung adenocarcinoma (LUAD). We examined the impact of knockdown (KD) of wild type (wt) U2AF1 and ectopic expression of two splice variant S34F mutant proteins in terms of alternative splicing (AS) pattern and cell cycle progression in A549 lung cancer cells. We demonstrate that induction of distinct AS events and disruption of mitosis at distinct sub-stages result from KD and ectopic expression of the mutant proteins. Importantly, when compared with the splicing pattern seen in LUAD patients with U2AF1 S34F mutation, ectopic expression of S34F mutants but not KD was shown to result in common AS events in several genes involved in cell cycle progression. Our study thus points to an active role of U2AF1 S34F mutant protein in inducing cell cycle dysregulation and mitotic stress. In addition, alternatively spliced genes which we describe here may represent novel potential markers of lung cancer development.
Choi, Boae,Choi, Mina,Park, Charny,Lee, Eun Kyung,Kang, Dong Hoon,Lee, Doo Jae,Yeom, Jae Yoon,Jung, Yeonjoo,Kim, Jaesang,Lee, Sanghyuk,Kang, Sang Won Oxford University Press 2015 Cardiovascular research Vol.106 No.3
<P><B>Aims</B></P><P>Pro-inflammatory response of vascular smooth muscle cells (VSMCs) is triggered by endothelial damage and a causative step for thrombosis and neointimal thickening in the injured arterial vessels. Therefore, we investigate a role of cytosolic Hsp60 as a novel pro-inflammatory mediator in VSMCs.</P><P><B>Methods and results</B></P><P>Hsp60 was detected in the cytosol of VSMCs. The selective depletion of cytosolic Hsp60 in VSMCs reduced the IκB kinase activation, repressed the induction of nuclear factor (NF)-κB-dependent survival genes (MnSOD and Bfl-1/A1), and enhanced apoptotic death in response to TNF-α. Moreover, a quantitative RNA sequencing revealed that the expression of 75 genes among the 774 TNF-α-inducible genes was significantly reduced by the depletion of cytosolic Hsp60. In particular, the expression of pro-inflammatory cytokines/chemokines, such as CCL2, CCL20, and IL-6, was regulated by the cytosolic Hsp60 in VSMCs. Finally, the depletion of cytosolic Hsp60 markedly inhibited the neointimal thickening in the balloon-injured arterial vessels by inducing apoptotic cell death and inhibiting chemokine production.</P><P><B>Conclusions</B></P><P>This study provides the first evidence that cytosolic Hsp60 could be a therapeutic target for preventing VSMC hyperplasia and inflammatory response in the injured vessels.</P>