DOCSLIB.ORG

Long Noncoding RNA MAFG-AS1 Facilitates the Progression of Hepatocellular Carcinoma Via Targeting Mir-3196/OTX1 Axis

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Long Noncoding RNA MAFG-AS1 Facilitates the Progression of Hepatocellular Carcinoma Via Targeting Mir-3196/OTX1 Axis European Review for Medical and Pharmacological Sciences 2020; 24: 12131-12143 Long noncoding RNA MAFG-AS1 facilitates the progression of hepatocellular carcinoma via targeting miR-3196/OTX1 axis Z.-Q. HU1,2, H.-C. LI2,3, F. TENG1,2, Q.-M. CHANG1,2, X.-B. WU1,2, J.-F. FENG1,2, Z.-P. ZHANG1,2 1Department of Hepatobiliary-Pancreatic Surgery, Minhang Hospital, Fudan University, Shanghai, China 2Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, Shanghai, China 3Department of Surgery, Minhang Hospital, Fudan University, Shanghai, China Zhiqiu Hu and Hongchang Li contributed equally to this work Abstract. – OBJECTIVE: Hepatocellular carci- Key Words: noma (HCC) is an invasive malignant tumor with MAFG-AS1, MiR-3196, OTX1, Hepatocellular carci- high mortality rate. Long non-coding RNA (ln- noma (HCC). cRNA) MAFG-AS1 has been showed to play an oncogenic role in several malignant tumors. Nonetheless, the exact role of MAFG-AS1 in the progression of HCC has not been fully elucidated. PATIENTS AND METHODS: Real-time quanti- Introduction tative polymerase chain reaction (RT-qPCR) and Western blot were used to detect the mRNA and Primary liver cancer is the second leading protein expression of MAFG-AS1 in HCC tissues cause of death around the world1. In recent years, and cells. Cell counting kit-8 (CCK-8), transwell the incidence of liver cancer has been on the rise, and tubule formation assays were applied to un- 2 cover the proliferation, migration, invasion and with about 3% in women and 4% in men . Hepa- tumor angiogenesis of HCC cells, respectively. tocellular carcinoma (HCC), the most typical sub- RNA binding protein immunoprecipitation (RIP) type of primary liver cancer, possesses high mor- assay and Luciferase reporter gene assay were bidity and mortality worldwide3. Currently, tran- employed to explore the molecular mechanism. scatheter arterial embolization (TAE) and tran- In addition, Xenograft assay was used to investi- scatheter chemotherapy embolization (TACE) are gate the effect of MAFG-AS1 in vivo. RESULTS: MAFG-AS1 was highly expressed the primary interventional therapies for HCC pa- in HCC tissues and cells. Attenuation of MAFG- tients. Hepatectomy is more effective for patients AS1 evidently suppressed the proliferation, mi- with HCC at an early stage and those with sat- gration, invasion and tumor angiogenesis of isfactory liver function, while TACE is recom- HCC cells, suggesting that MAFG-AS1 played an mended for patients with advanced HCC4. Al- oncogenic role in HCC. MiR-3196 was sponged though it has been reported that TACE is more by MAFG-AS1, and OTX1 was a downstream tar- 5 get of miR-3196 in HCC. In addition, OTX1 ex- effective in the treatment of 3-5 cm tumors , the pression was negatively associated with miR- long-term survival rate of patients is still far from 3196 but positively associated with MAFG-AS1 satisfactory. TACE or TAE cannot significant- in HCC tissues. Overexpression of OTX1 could ly improve the survival rate of patients with liv- abolish the repressive influence of MAFG-AS1 er cancer in the middle stage6. Besides, the 5-year inhibition on the proliferation, migration, inva- survival rate of HCC patients is lower than 10%, sion and tumor angiogenesis of HCC cells. which remains dismal7. Therefore, it is meaning- CONCLUSIONS: MAFG-AS1 facilitated the progression of HCC via targeting miR-3196/ ful to explore the potential molecular mechanism OTX1 axis, which might be used as a new insight of HCC development and to uncover more effi- for HCC treatment. cient therapeutic targets. Corresponding Author: Ziping Zhang, MD; e-mail: [email protected] 12131 Z.-Q. Hu, H.-C. Li, F. Teng, Q.-M. Chang, X.-B. Wu, J.-F. Feng, Z.-P. Zhang Long noncoding RNAs (lncRNAs) are a type Cell Culture of RNA transcripts implicated in various bio- Human normal liver cell line L02 and human logical processes, such as cell proliferation, mi- HCC cell lines (HCCLM3, Hep3B, Huh7 and gration, invasion and apoptosis8,9. They serve as MHCC97-H) were obtained from Shanghai In- vital factors in malignant tumors. Of note, ln- stitutes for Biological Sciences, Chinese Acade- cRNA LINC01197, regulated by FOXO1, inhib- my of Sciences (Shanghai, China). All cells were its the proliferation of pancreatic adenocarcinoma cultured in Dulbeccoʼs Modified Eagleʼs Medi- cells via inactivating Wnt/β-catenin signaling10. um (DMEM) medium (Invitrogen, Carlsbad, CA, LINC00612 promotes the proliferation and in- USA) containing 100 μg/mL streptomycin, 100 U/ vasion of bladder cancer cells via sponging miR- mL penicillin, and 10% fetal bovine serum (FBS) 590 to upregulate PHF14 expression11. LncRNA (Gibco, Rockville, MD, USA) in an incubator at ZEB1-AS1 promotes the migration, invasion and 37°C with 5% CO2. proliferation, and inhibits the apoptosis of blad- der cancer as a competing endogenous RNA via Cell Transfection elevating the expression of fascin-1 by spong- Short hairpin RNA targeting MAFG-AS1 (sh- ing miR-200b12. HOXD-AS1 facilitates the epi- MAFG-AS1#1, sh-MAFG-AS1#2 and sh-MAFG- thelial to mesenchymal transition of ovarian can- AS1#3) and sh-NC were synthesized from San- cer cells through sponging miR-186-5p and regu- gon Biotech (Shanghai, China). For overexpres- lating PIK3R313. LncRNA MAFG-AS1 has also sion of miR-3196, miR-3196 mimics and NC mim- been confirmed to play a significant role in sever- ics were transfected into HCC cells. For overex- al malignancies. Sui et al14 has demonstrated that pression of OTX1, pcDNA3.1 vector (Genechem MAFG-AS1 aggravates the proliferation of lung Company, Shanghai, China) was subcloned with adenocarcinoma cells through targeting miR- OTX1 to construct pcDNA3.1/OTX1 vector. 744-5p/MAFG axis. MAFG-AS1 enhances the Empty pcDNA3.1 vector was employed as a neg- development of breast carcinoma via regulating ative control. Cell transfection was performed ac- miR-339-5p/MMP15 axis15. MAFG-AS1 drives cording to the instructions of Lipofectamine 2000 the progression of colorectal cancer by sponging (Invitrogen, Carlsbad, CA, USA). After 48 h of miR-147b and enhancing the expression of NDU- transfection, the cells were collected for subse- FA416. Nevertheless, the exact role of MAFG-AS1 quent experiments. in the progression of HCC and the possible under- lying mechanism have not been fully elucidated. Cell Proliferation Assay In the present study, we aimed to unveil the The viability of MHCC97-H and Huh7 cells role and function of MAFG-AS1 in HCC progres- was detected in strict accordance with cell count- sion. The results indicated that MAFG-AS1 facil- ing kit-8 (CCK-8) assay. Briefly, transfected cells itated the progression of HCC via targeting miR- were first seeded into 96-well plates, and cultured 3196/OTX1 axis. All our findings suggested that for 0 h, 24 h, 48 h, 72 h, and 96 h, respectively. MAFG-AS1 might become a promising therapeu- At appointed time points, 10 μL of CCK-8 reagent tic target for the treatment of HCC. (Dojindo Molecular Technologies, Kumamoto, Japan) was added to each well, followed by incu- bation for 4 h in the dark. Absorbance at 450 nm was finally evaluated by a micro-plate reader. Patients and Methods Transwell Assay Patients and Tissue Specimens The migration and invasion of HCC cells This investigation was approved by the Re- were examined by the use of chambers coated or search Ethics committee of Minhang Hospital, non-coated with Matrigel, respectively. Briefly, Fudan University. HCC tissues and adjacent nor- cells were plated into the upper chamber with se- mal tissues were obtained from patients. The se- rum-free DMEM. Meanwhile, complete DMEM lection of patients was based on the guideline pro- with 10% FBS was added to the lower chamber as posed by the Union for International Cancer Con- chemoattractant. After 24 h of incubation, cells trol (UICC). All patients did not receive adjuvant migrated or invaded through the membrane to the radiotherapy, chemotherapy, or immunotherapy lower chamber were stained with 0.1% crystal vi- before surgery. Informed written consent was ob- olet. Finally, the number of migrated or invaded tained from patients before the study. cells was counted under an inverted microscope 12132 Long noncoding RNA MAFG-AS1 in hepatocellular carcinoma (Olympus, Tokyo, Japan). 5 fields of view were tion Kit (Applied Biosystems, Foster City, CA, randomly selected for each sample. USA). Glyceraldehyde 3-phosphate dehydroge- nase (GAPDH) and U6 were used as internal refer- RNA Binding Protein ences for MAFG-AS1 and OTX1, and miR-3196, Immunoprecipitation (RIP) Assay respectively. The relative expression of genes was RIP assay was conducted according to the in- calculated by the 2-ΔΔCt method. Primer sequenc- structions of a Magna RIP RNA-Binding Pro- es used in this study were as follows: MAFG- tein Immunoprecipitation reagent kit (Merck AS1 forward: 5’-ATGACGACCCCCAATA- Millipore, Billerica, MA, USA). HCC cells were AAGGA-3’, and reverse: 5’-CACCGACATG- lysed in RIP buffer and incubated with magnetic GTTACCAGC-3’; miR-3196 forward: 5’-CCT- beads conjugated to Ago2 antibody (ab32381; Ab- GTGTATGCATCCTCGACTG-3’, and reverse: cam Inc., Cambridge, MA, USA) or IgG antibody 5’-CTGGCGTGTAATGGAGTCG-3’; OTX1 (ab172730; 1:5000; Abcam Inc., Cambridge, MA, forward: 5′-CTGCTCTTCCTCAATCAAT- USA). Finally, immunoprecipitated RNAs were GG-3′, and reverse: 5′-ACCCTGACTTGTCT- evaluated by real-time quantitative polymerase GTTTCC-3′; GAPDH forward: 5′-ATGGGAC- chain reaction (RT-qPCR). GATGCTGGTACTGA-3′, and reverse: 5′-TGCT- GACAACCTTGAGTGAAAT-3′;
Load more

Recommended publications
  • Lncrna MAFG-AS1 Promotes the Aggressiveness of Breast Carcinoma Through Regulating Mir-339-5P/MMP15
    European Review for Medical and Pharmacological Sciences 2019; 23: 2838-2846 LncRNA MAFG-AS1 promotes the aggressiveness of breast carcinoma through regulating miR-339-5p/MMP15 H. LI1, G.-Y. ZHANG2, C.-H. PAN3, X.-Y. ZHANG1, X.-Y. SU4 1Department of Obstetrics and Gynecology, Shandong Jiyang Public Hospital, Ji’nan, Shandong, China 2Department of Anesthesiology, Shandong Jiyang Public Hospital, Ji’nan, Shandong, China 3Department of Obstetrics and Gynecology, LanCun central hospital, Jimo, Shandong, China 4Department of Critical Care Medicine, Tai’an Central Hospital, Tai’an, Shandong, China Abstract. – OBJECTIVE: The main purposes of and is the leading cause of cancer-related deaths this study are to investigate the possible effects worldwide1. Recently, treatment strategies, such of long noncoding RNAs (lncRNAs) MAFG-AS1 on as chemotherapy, radiotherapy and molecular tar- the growth and metastasis of breast carcinoma. PATIENTS AND METHODS: geting treatment significantly improve the thera- The quantitative 2 Real Time-Polymerase Chain Reaction (qRT- peutic outcome of patients . However, the clinical PCR) assay was used to assess the MAFG-AS1 outcome of patients with breast cancer needs to level in breast cancer tissues and cells. The improve. The metastasis of cancer cells is one ma- wound healing and transwell invasion analy- jor difficulty of overcoming the poor prognosis of sis were applied to explore the invasion and mi- breast cancer patients. The epithelial-mesenchy- gration of breast cancer cell in vitro. The ex- mal transition (EMT) process of cancer cells is a pressions of epithelial-mesenchymal transition 3,4 (EMT) related markers were determined by West- crucial step during metastasis .
    [Show full text]
  • C/EBP Creates Elite Cells for Ipsc Reprogramming by Upregulating
    ARTICLES C/EBPα creates elite cells for iPSC reprogramming by upregulating Klf4 and increasing the levels of Lsd1 and Brd4 Bruno Di Stefano1,2,8,9,10, Samuel Collombet3,8, Janus Schou Jakobsen4,5,6,8, Michael Wierer7, Jose Luis Sardina1,2, Andreas Lackner1,2,9, Ralph Stadhouders1,2, Carolina Segura-Morales1,2, Mirko Francesconi1,2, Francesco Limone1,2, Matthias Mann7, Bo Porse4,5,6, Denis Thieffry3 and Thomas Graf1,2,10 Reprogramming somatic cells into induced pluripotent stem cells (iPSCs) is typically inefficient and has been explained by elite-cell and stochastic models. We recently reported that B cells exposed to a pulse of C/EBPα (Bα0 cells) behave as elite cells, in that they can be rapidly and efficiently reprogrammed into iPSCs by the Yamanaka factors OSKM. Here we show that C/EBPα post-transcriptionally increases the abundance of several hundred proteins, including Lsd1, Hdac1, Brd4, Med1 and Cdk9, components of chromatin-modifying complexes present at super-enhancers. Lsd1 was found to be required for B cell gene silencing and Brd4 for the activation of the pluripotency program. C/EBPα also promotes chromatin accessibility in pluripotent cells and upregulates Klf4 by binding to two haematopoietic enhancers. Bα0 cells share many properties with granulocyte/macrophage progenitors, naturally occurring elite cells that are obligate targets for leukaemic transformation, whose formation strictly requires C/EBPα. The ability to reprogram somatic into pluripotent cells has revolu- complex process, where multiple players synergistically establish new tionized stem cell research with major implications for almost all transcriptional networks and remove epigenetic barriers14. Among the fields of modern biology.
    [Show full text]
  • Picosecond-Hetero-FRET Microscopy to Probe Protein-Protein Interactions in Live Cells
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector 3570 Biophysical Journal Volume 83 December 2002 3570–3577 Picosecond-Hetero-FRET Microscopy to Probe Protein-Protein Interactions in Live Cells Marc Tramier,* Isabelle Gautier,* Tristan Piolot,† Sylvie Ravalet,‡ Klaus Kemnitz,† Jacques Coppey,* Christiane Durieux,* Vincent Mignotte,‡ and Maı¨te´ Coppey-Moisan* *Institut Jacques Monod, UMR 7592, CNRS, Universite´s P6/P7, 75251 Paris Cedex 05, France; †EuroPhoton GmbH, D-12247, Berlin, Germany; and ‡ICGM, Department of Hematology, Maternite´ Port-Royal, 75014 Paris, France ABSTRACT By using a novel time- and space-correlated single-photon counting detector, we show that fluorescence resonance energy transfer (FRET) between cyan fluorescent protein (CFP) and yellow fluorescent protein (YFP) fused to herpes simplex virus thymidine kinase (TK) monomers can be used to reveal homodimerization of TK in the nucleus and cytoplasm of live cells. However, the quantification of energy transfer was limited by the intrinsic biexponential fluorescence decay of the donor CFP (lifetimes of 1.3 Ϯ 0.2 ns and 3.8 Ϯ 0.4 ns) and by the possibility of homodimer formation between two TK-CFP. In contrast, the heterodimerization of the transcriptional factor NF-E2 in the nucleus of live cells was quantified from the analysis of the fluorescence decays of GFP in terms of 1) FRET efficiency between GFP and DsRed chromophores fused to p45 and MafG, respectively, the two subunits of NF-E2 (which corresponds to an interchromophoric distance of 39 Ϯ 1 Å); and 2) fractions of GFP-p45 bound to DsRed-MafG (constant in the nucleus, varying in the range of 20% to 70% from cell to cell).
    [Show full text]
  • Human Small Maf Proteins Form Heterodimers with CNC Family Transcription Factors and Recognize the NF-E2 Motif
    Oncogene (1997) 14, 1901 ± 1910 1997 Stockton Press All rights reserved 0950 ± 9232/97 $12.00 Human small Maf proteins form heterodimers with CNC family transcription factors and recognize the NF-E2 motif Tsutomu Toki1, Jugou Itoh2, Jun'ichi Kitazawa1, Koji Arai1, Koki Hatakeyama3, Jun-itsu Akasaka4, Kazuhiko Igarashi5, Nobuo Nomura6, Masaru Yokoyama1, Masayuki Yamamoto5 and Etsuro Ito1 1Department of Pediatrics, 2Medicine, School of Medicine; 3Department of Biology, Faculty of Sciences, Hirosaki University, Hirosaki 036; 4Department of Biochemistry, Tohoku University School of Medicine, Sendai 980-77; 5Center for TARA and Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba 305; 6Kazusa DNA Institute, Kisarazu 292, Japan The transcription factor NF-E2, a heterodimeric protein Talbot et al., 1990; Talbot and Grosveld, 1991; complex composed of p45 and small Maf family Kotkow and Orkin, 1995). Recent analyses demon- proteins, is considered crucial for the regulation of strated that NF-E2 is composed of two subunits erythroid gene expression and platelet formation. To (Andrews et al., 1993a,b; Igarashi et al., 1994). The facilitate the characterization of NF-E2 functions in large p45 subunit belongs to a family of basic leucine- human cells, we isolated cDNAs encoding two members zipper (bZip) proteins that is closely related to the of the small Maf family, MafK and MafG. The human Drosophila Cap`n'colar (the CNC family) factor mafK and mafG genes encode proteins of 156 and 162 (Mohler et al., 1991). It cannot bind to the NF-E2 amino acid residues, respectively, whose deduced amino sequence as a homodimer, but does do after forming acid sequences show approximately 95% identity to their heterodimers with chicken small Maf family proteins, respective chicken counterparts.
    [Show full text]
  • Micrornas As Modulators of Smoking-Induced Gene Expression Changes in Human Airway Epithelium
    MicroRNAs as modulators of smoking-induced gene expression changes in human airway epithelium Frank Schembria,1, Sriram Sridharb,1, Catalina Perdomoc, Adam M. Gustafsond, Xiaoling Zhangd, Ayla Ergune, Jining Lua, Gang Liua, Xiaohui Zhanga, Jessica Bowersf, Cyrus Vazirib, Kristen Ottc, Kelly Sensingerf, James J. Collinse, Jerome S. Brodya, Robert Gettsf, Marc E. Lenburga,b,d, and Avrum Spiraa,b,d,2 aPulmonary Center, bDepartment of Pathology and Laboratory Medicine, and cGenetics and Genomics Graduate Program, Boston University School of Medicine, Boston, MA 02118; dBioinformatics Program, Boston University School of Engineering, Boston, MA 02215; eDepartment of Biomedical Engineering and Center for BioDynamics and Howard Hughes Medical Institute, Boston University, Boston, MA 02215; and fGenisphere, Inc., Hatfield, PA 19440 Edited by Charles R. Cantor, Sequenom Inc., San Diego, CA, and approved November 21, 2008 (received for review July 3, 2008) We have shown that smoking impacts bronchial airway gene Hundreds of human miRNAs have been cloned (11), with each of expression and that heterogeneity in this response associates with them predicted to regulate hundreds of genes by complementary smoking-related disease risk. In this study, we sought to determine binding to the 3Ј-untranslated region (UTR) of target mRNAs (12). whether microRNAs (miRNAs) play a role in regulating the airway A number of miRNAs have been shown to play important roles in gene expression response to smoking. We examined whole-ge- developmental timing, cell death, carcinogenesis, and stress responses in nome miRNA and mRNA expression in bronchial airway epithelium vitro (13–16), such as hypoxia (17). Whereas miRNA expression has and found 28 miRNAs to been examined in lung tumors (18–24), neither the expression of (20 ؍ from current and never smokers (n be differentially expressed (P < 0.05) with the majority being miRNA in bronchial epithelium nor the effect of smoking on bronchial down-regulated in smokers.
    [Show full text]
  • Metabolic Profiling of Cancer Cells Reveals Genome-Wide
    ARTICLE https://doi.org/10.1038/s41467-019-09695-9 OPEN Metabolic profiling of cancer cells reveals genome- wide crosstalk between transcriptional regulators and metabolism Karin Ortmayr 1, Sébastien Dubuis1 & Mattia Zampieri 1 Transcriptional reprogramming of cellular metabolism is a hallmark of cancer. However, systematic approaches to study the role of transcriptional regulators (TRs) in mediating 1234567890():,; cancer metabolic rewiring are missing. Here, we chart a genome-scale map of TR-metabolite associations in human cells using a combined computational-experimental framework for large-scale metabolic profiling of adherent cell lines. By integrating intracellular metabolic profiles of 54 cancer cell lines with transcriptomic and proteomic data, we unraveled a large space of associations between TRs and metabolic pathways. We found a global regulatory signature coordinating glucose- and one-carbon metabolism, suggesting that regulation of carbon metabolism in cancer may be more diverse and flexible than previously appreciated. Here, we demonstrate how this TR-metabolite map can serve as a resource to predict TRs potentially responsible for metabolic transformation in patient-derived tumor samples, opening new opportunities in understanding disease etiology, selecting therapeutic treat- ments and in designing modulators of cancer-related TRs. 1 Institute of Molecular Systems Biology, ETH Zurich, Otto-Stern-Weg 3, CH-8093 Zurich, Switzerland. Correspondence and requests for materials should be addressed to M.Z. (email: [email protected]) NATURE COMMUNICATIONS | (2019) 10:1841 | https://doi.org/10.1038/s41467-019-09695-9 | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-019-09695-9 ranscriptional regulators (TRs) are at the interface between implemented by the additional quantification of total protein the cell’s ability to sense and respond to external stimuli or abundance and is based on the assumption that protein content T 1 changes in internal cell-state .
    [Show full text]
  • Engineered Type 1 Regulatory T Cells Designed for Clinical Use Kill Primary
    ARTICLE Acute Myeloid Leukemia Engineered type 1 regulatory T cells designed Ferrata Storti Foundation for clinical use kill primary pediatric acute myeloid leukemia cells Brandon Cieniewicz,1* Molly Javier Uyeda,1,2* Ping (Pauline) Chen,1 Ece Canan Sayitoglu,1 Jeffrey Mao-Hwa Liu,1 Grazia Andolfi,3 Katharine Greenthal,1 Alice Bertaina,1,4 Silvia Gregori,3 Rosa Bacchetta,1,4 Norman James Lacayo,1 Alma-Martina Cepika1,4# and Maria Grazia Roncarolo1,2,4# Haematologica 2021 Volume 106(10):2588-2597 1Department of Pediatrics, Division of Stem Cell Transplantation and Regenerative Medicine, Stanford School of Medicine, Stanford, CA, USA; 2Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford School of Medicine, Stanford, CA, USA; 3San Raffaele Telethon Institute for Gene Therapy, Milan, Italy and 4Center for Definitive and Curative Medicine, Stanford School of Medicine, Stanford, CA, USA *BC and MJU contributed equally as co-first authors #AMC and MGR contributed equally as co-senior authors ABSTRACT ype 1 regulatory (Tr1) T cells induced by enforced expression of interleukin-10 (LV-10) are being developed as a novel treatment for Tchemotherapy-resistant myeloid leukemias. In vivo, LV-10 cells do not cause graft-versus-host disease while mediating graft-versus-leukemia effect against adult acute myeloid leukemia (AML). Since pediatric AML (pAML) and adult AML are different on a genetic and epigenetic level, we investigate herein whether LV-10 cells also efficiently kill pAML cells. We show that the majority of primary pAML are killed by LV-10 cells, with different levels of sensitivity to killing. Transcriptionally, pAML sensitive to LV-10 killing expressed a myeloid maturation signature.
    [Show full text]
  • A MAFG-Lncrna Axis Links Systemic Nutrient Abundance to Hepatic Glucose Metabolism
    ARTICLE https://doi.org/10.1038/s41467-020-14323-y OPEN A MAFG-lncRNA axis links systemic nutrient abundance to hepatic glucose metabolism Marta Pradas-Juni et al.# Obesity and type 2 diabetes mellitus are global emergencies and long noncoding RNAs (lncRNAs) are regulatory transcripts with elusive functions in metabolism. Here we show that a high fraction of lncRNAs, but not protein-coding mRNAs, are repressed during diet-induced 1234567890():,; obesity (DIO) and refeeding, whilst nutrient deprivation induced lncRNAs in mouse liver. Similarly, lncRNAs are lost in diabetic humans. LncRNA promoter analyses, global cistrome and gain-of-function analyses confirm that increased MAFG signaling during DIO curbs lncRNA expression. Silencing Mafg in mouse hepatocytes and obese mice elicits a fasting-like gene expression profile, improves glucose metabolism, de-represses lncRNAs and impairs mammalian target of rapamycin (mTOR) activation. We find that obesity-repressed LincIRS2 is controlled by MAFG and observe that genetic and RNAi-mediated LincIRS2 loss causes elevated blood glucose, insulin resistance and aberrant glucose output in lean mice. Taken together, we identify a MAFG-lncRNA axis controlling hepatic glucose metabolism in health and metabolic disease. #A full list of authors and their affiliations appears at the end of the paper. NATURE COMMUNICATIONS | (2020) 11:644 | https://doi.org/10.1038/s41467-020-14323-y | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-020-14323-y ellular and organism-level energy homeostasis and nutri- by MAFG and CRISPR–Cas9-mediated knockout, or antisense- Cent partitioning are instrumental for survival. In higher mediated RNA interference of LincIRS2 causes hyperglycemia, organisms, multi-organ systems evolved to react to shifts insulin resistance, likely caused by alterations in glucogenic in energy supply by storing (anabolic) or metabolizing (catabolic) gene expression in lean mice.
    [Show full text]
  • The Cataract-Linked RNA-Binding Protein Celf1 Post-Transcriptionally
    The cataract-linked RNA-binding protein Celf1 post-transcriptionally controls the spatiotemporal expression of the key homeodomain transcription factors Pax6 and Prox1 in lens development Sandeep Aryal, Justine Viet, Bailey a T Weatherbee, Archana D. Siddam, Francisco José García-Hernández, Carole Gautier-Courteille, Luc Paillard, Salil A. Lachke To cite this version: Sandeep Aryal, Justine Viet, Bailey a T Weatherbee, Archana D. Siddam, Francisco José García- Hernández, et al.. The cataract-linked RNA-binding protein Celf1 post-transcriptionally controls the spatiotemporal expression of the key homeodomain transcription factors Pax6 and Prox1 in lens development. Human Genetics, Springer Verlag, 2020, 139 (12), pp.1541-1554. 10.1007/s00439-020- 02195-7. hal-02888615 HAL Id: hal-02888615 https://hal.archives-ouvertes.fr/hal-02888615 Submitted on 10 Jul 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. The cataract-linked RNA-binding protein Celf1 post-transcriptionally controls the spatiotemporal expression of the key homeodomain transcription
    [Show full text]
  • MAFB Promotes Cancer Stemness and Tumorigenesis in Osteosarcoma Through a Sox9-Mediated Positive Feedback Loop
    Author Manuscript Published OnlineFirst on March 31, 2020; DOI: 10.1158/0008-5472.CAN-19-1764 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. MAFB promotes cancer stemness and tumorigenesis in osteosarcoma through a Sox9-mediated positive feedback loop Yanyan Chen1,†, Bin Wang2, †, Mengxi Huang1, †, Tao Wang 2, †, Chao Hu 3,†, Qin Liu 2, Dong Han 4, Cheng Chen1, Junliang Zhang5, Zhiping Li4, Chao Liu 6, Wenbin Lei 7,Yue Chang1, Meijuan Wu1,Dan Xiang1, Yitian Chen1, Rui Wang1, Weiqian Huang5, Zengjie Lei1 ,* and Xiaoyuan Chu1, * 1 Department of Medical Oncology, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu Province, People’s Republic of China 2 Department of Gastroenterology, Daping Hospital, Third Military Medical University (Ar- my Medical University), Chongqing, People’s Republic of China 3 Department of Orthopedics, 904 Hospital of PLA, North Xingyuan Road, Beitang Dis- trict, Wuxi, Jiangsu, People’s Republic of China 4 Department of Medical Oncology, Jinling Hospital, Nanjing Clinical School of Southern Medical University, Nanjing, Jiangsu Province, People’s Republic of China 5 Department of Orthopedics, Affiliated Jinling Hospital, Medical School of Nanjing Univer- sity, Nanjing, Jiangsu Province, People’s Republic of China 6 Department of Medical Oncology, Jinling Hospital, Nanjing Clinical School of Nanjing Medical University, Nanjing, Jiangsu Province, People’s Republic of China 7Department of Orthopedics, Tianshui Cooperation of Chinese and Western Medicine Hospi- tal, Tianshui, Gansu Province, People’s Republic of China * To whom correspondence should be addressed. Xiaoyuan Chu, Tel: +86-25-80860131, Fax: +86-25-80860131, Email: [email protected]; Zengjie Lei, Email: leiz- [email protected] ; †The authors wish it to be known that, in their opinion, the first five authors should be regard- ed as joint First Authors.
    [Show full text]
  • C D B a Mafg Mafk Maff
    KCTD13 PROX1 IRF3 KLRG1 TJP1 COL12A1 LMBRD2 SLC25A32 TRO RASD1 HECW2 CXCR4 IRF2BPL PTPDC1 CD55 PSAT1 A MOV10L1SPRED2 TSGA10 BAIAP2 SLC1A4 TMEM39A PPAP2B BCL3 ARL4A RAPGEF1 VEGFC F3 PHLDB2 UNC5B PRDM1 LEPREL1 NR4A2 NR4A1 RAPH1 SOCS6 SULT1B1 TNFAIP3 RGS2 GIMAP1 KIAA0513 STEAP2 HSP90B1 MAP3K8 SLC25A25 TNFRSF1B DDIT4 PLEKHA1 FRMD6 C2CD4A TSPAN11 IGIP UACA RFX2 PMAIP1 IL15RA SLC2A12 MOSPD1 GIMAP6 EDN1 ADAM19 NCOA7 CLDN5 CHSY3 BCAP29 PDP1 UBE2J1 RBPMS2 PPFIBP2 KAT2B PLAU SIPA1L3 FOXN3 C14orf93 KIF26A EGR1 ACER2 MEI1 GAB1 ASUN CNN3 SIRT1 RALGPS2 PPM1H TOX2 FAM174A DNAJB4 KLF11 GBE1 CHN2 TRIM2 IL1R1 KCNJ2 TFPI2 KLF2 PPP1R3B PPARA PPP1R15B VEGFA DSE CCRN4L NR2F2 AXL EXOC8 CCNA1 B4GALT1 GIMAP7 RQCD1 ITPRIP MYADM ICAM3 FGF2 HEY1 NFIL3 CTH PTP4A3 ATP2B1 EXT1 KLHL3 KLF9 COL13A1 MID2 GDPD1 EHD3 STRBP P4HA1 OSBP2 SEC11C NFAT5 PDGFD ENC1 DUSP5 NRCAM ANO6 KLF10 SLC40A1 C2CD4B MEIS1HOXB2_ELF1 GIMAP2 SEMA6A NR4A3 KDM6B MYO1D FAM193A CSRNP2 RASGRF2 APOO ESYT2 NINL FOXP1 HDAC9 CLK1 CDK6 SCAMP5 PHLDB3 ASGR1 HELLS DIEXF SULT1C4 MBNL1 TRAF5 GIMAP8 FOXJ2_ELF1 SIX4 TEAD4_ERG ARL4C EGR3 BACH1 ITGA6 LRRC8B MFSD2A SLC4A7 RDX PLAT PODXL USF2 NR5A2 RALGAPA2 DDX60L ANGPT2 CSF1 FOXO1_ELF1 ATP1B1 CTCF P4HA3 DNAJC3 CREG1 ACRBP BRAT1 RHOBTB1 TEAD2 ARID5A FBXL2 SLC12A4 SPRY4 CDC14A ATF3 ETV5_HOXA2 CHST11 GCNT1 ESM1 FZD8 IVNS1ABP MGP CROCC SLC39A14 DUSP7 MAP2K6 TOB2 SLC35G2 SPTY2D1 BMP4 ERG ST8SIA4 POLI MCL1 SOX13 CROT CGNL1 MXD1 ETS1 THBD BACH2 ELF1 PLAUR STC1 SGK3 ITPR2 IRAK2 PHC3 FAM198B AIM1 RNF122 ETV3 FKBP14 PIM1 MX1 TNIK MMP10 ST3GAL5 DUSP1 GULP1 INPP5A PSTPIP2 MEF2C
    [Show full text]
  • Induction of Therapeutic Tissue Tolerance Foxp3 Expression Is
    Downloaded from http://www.jimmunol.org/ by guest on October 2, 2021 is online at: average * The Journal of Immunology , 13 of which you can access for free at: 2012; 189:3947-3956; Prepublished online 17 from submission to initial decision 4 weeks from acceptance to publication September 2012; doi: 10.4049/jimmunol.1200449 http://www.jimmunol.org/content/189/8/3947 Foxp3 Expression Is Required for the Induction of Therapeutic Tissue Tolerance Frederico S. Regateiro, Ye Chen, Adrian R. Kendal, Robert Hilbrands, Elizabeth Adams, Stephen P. Cobbold, Jianbo Ma, Kristian G. Andersen, Alexander G. Betz, Mindy Zhang, Shruti Madhiwalla, Bruce Roberts, Herman Waldmann, Kathleen F. Nolan and Duncan Howie J Immunol cites 35 articles Submit online. Every submission reviewed by practicing scientists ? is published twice each month by Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts http://jimmunol.org/subscription http://www.jimmunol.org/content/suppl/2012/09/17/jimmunol.120044 9.DC1 This article http://www.jimmunol.org/content/189/8/3947.full#ref-list-1 Information about subscribing to The JI No Triage! Fast Publication! Rapid Reviews! 30 days* Why • • • Material References Permissions Email Alerts Subscription Supplementary The Journal of Immunology The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2012 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. This information is current as of October 2, 2021.
    [Show full text]