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TNF Expression Noncoding Rnas and LRRFIP1 Regulate Noncoding RNAs and LRRFIP1 Regulate TNF Expression Lihua Shi, Li Song, Michael Fitzgerald, Kelly Maurer, Asen Bagashev and Kathleen E. Sullivan This information is current as of September 26, 2021. J Immunol published online 24 February 2014 http://www.jimmunol.org/content/early/2014/02/21/jimmun ol.1302063 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2014/02/21/jimmunol.130206 Material 3.DCSupplemental Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 26, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2014 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published February 24, 2014, doi:10.4049/jimmunol.1302063 The Journal of Immunology Noncoding RNAs and LRRFIP1 Regulate TNF Expression Lihua Shi, Li Song, Michael Fitzgerald, Kelly Maurer, Asen Bagashev,1 and Kathleen E. Sullivan Noncoding RNAs have been implicated in the regulation of expression of numerous genes; however, the mechanism is not fully understood. We identified bidirectional, long noncoding RNAs upstream of the TNF gene using five different methods. They arose in a region where the repressors LRRFIP1, EZH2, and SUZ12 were demonstrated to bind, suggesting a role in repression. The noncoding RNAs were polyadenylated, capped, and chromatin associated. Knockdown of the noncoding RNAs was associated with derepression of TNF mRNA and diminished binding of LRRFIP1 to both RNA targets and chromatin. Overexpression of the non- coding RNAs led to diminished expression of TNF and recruitment of repressor proteins to the locus. One repressor protein, LRRFIP1, bound directly to the noncoding RNAs. These data place the noncoding RNAs upstream of TNF gene as central to the transcriptional regulation. They appear to serve as a platform for the assembly of a repressive complex. The Journal of Immunology, 2014, 192: 000–000. Downloaded from umor necrosis factor is a member of a family of proteins TNF mRNA turnover (32–34). Collectively, these studies dem- that regulate immunologically competent cells. It is pre- onstrate that the regulation of TNF is rigorous and redundant, T dominantly produced by myeloid cells, activated T cells, presumably to limit the adverse consequences related to under- or and NK cells. The major roles of TNF include killing of tumor overexpression. cells, the induction of adhesion molecule expression at sites of In our studies of chromatin at the TNF locus, we identified http://www.jimmunol.org/ inflammation, stimulation of bone resorption, induction of fever, a region 300 bp upstream of the transcriptional start site (TSS) and activation of B cells, neutrophils, and monocytes (1–3). TNF where the majority of the transcriptionally relevant histone mod- inhibition is used therapeutically for arthritis and inflammatory ifications were found (19). We also identified a transcriptional bowel disease, and inhibition is associated with an increased risk repressor called LRRFIP1 (previously called GCF2) (35). Further of infection (4–8). Conversely, overexpression of TNF in murine evidence that this region might be important in the regulation of models is associated with pathologic inflammation (9–14). Thus, TNF came from a study of patients with systemic lupus erythe- regulation of TNF is of paramount importance. matosus, which found that the histone modifications at this site TNF is regulated at the level of chromatin, transcription, splicing, were different in patients compared with controls (36). This led us message turnover, and cleavage from the membrane (15–19). DNA to examine the upstream region of the TNF promoter more care- by guest on September 26, 2021 methylation inhibitors and histone deacetylase inhibitors can in- fully. We found significant levels of noncoding RNAs (ncRNAs) duce TNF expression, supporting a role for chromatin in the that mapped to this region. regulation of TNF transcription (19–21). Priming of TNF tran- ncRNAs are common in the genome, with ∼8000 identified (37). scription requires PU.1 and CEBP proteins, as is true for most In general, their abundance, conservation, and correlation with lineage-specific transcripts in monocytes (22–25). After stimula- transcription have argued for functionality, but there are relatively tion, NF-kB, AP1, and ETS family members bind to specific few specific examples known (38–41). The best-known ncRNA promoter motifs and drive active elongation (26–28). As is true for that regulates chromatin conformation is Xist, which coats the many highly inducible genes, message turnover is highly regulated X-chromosome destined for inactivation (42, 43). Long noncoding with tristetraprolin and TIA-1, predominantly responsible for RNAs have been implicated in pluripotency and innate immune destabilizing and repressing translation, respectively (10, 29–31). responses (44–46). Several studies have found that chromatin- HuR, TIAR, KSRP, and microRNAs have also been implicated in associated RNAs are bound to chromatin-modifying complexes on chromatin, suggesting a role in epigenetic regulation (47–49). In general, the ncRNA is thought to confer locus specificity and Division of Allergy Immunology, Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA 19104 alter local histone modifications, but the specific mechanisms for 1Current address: Molecular Studies of Neurodegenerative Diseases Laboratory, Fels each gene appear to be diverse and are largely not understood Institute for Cancer Research and Molecular Biology, School of Medicine, Temple (50, 51). University, Philadelphia, PA. Several groups have manipulated ncRNAs in an effort to dissect Received for publication August 9, 2013. Accepted for publication January 12, 2014. their exact function. The most common model is one in which the This work was supported by National Institutes of Health Grants 1RO1 AI 51323 and ncRNAs regulate H3K9me2 and H3K27me3 marks in cis and R21 AI090914 and the Wallace Chair of Pediatrics. mediate transcriptional repression (52–58). Nevertheless, a recent Address correspondence and reprint requests to Dr. Kathleen E. Sullivan, Division study found that many ncRNAs regulate gene expression in trans, of Allergy Immunology, Children’s Hospital of Philadelphia, 3615 Civic Center Boulevard, Philadelphia, PA 19104. E-mail address: [email protected] suggesting that there are many more mechanisms yet to be iden- The online version of this article contains supplemental material. tified (45). Despite the rapid increase in our understanding of Abbreviations used in this article: ChIP, chromatin immunoprecipitation; IRF1, IFN RNA-mediated transcriptional repression, much remains to be regulatory factor 1; LTA, lipoteichoic acid; ncRNA, noncoding RNA; qRT-PCR, learned regarding the mechanisms of repression. quantitative RT-PCR; RIP, receptor interacting protein; RNA-IP, RNA immunopre- This study was undertaken to examine ncRNAs upstream of the cipitation; shRNA, short hairpin RNA; TSS, transcriptional start site. TNF gene. We found a tightly linked choreography of ncRNAs Copyright Ó 2014 by The American Association of Immunologists, Inc. 0022-1767/14/$16.00 and repressors on intergenic chromatin upstream of TNF. Further- www.jimmunol.org/cgi/doi/10.4049/jimmunol.1302063 2 NONCODING RNA REGULATION OF TNF EXPRESSION more, we identified a novel function of the transcriptional repressor K562 RNA, according to the manufacturer’s recommendation. The RNA LRRFIP1. extracted from the supernatant or wash buffer was used as a negative control. Controls using 18S (noncapped, nonpolyadenylated) and IL-1b (capped, polyadenylated) were used to confirm the appropriate recovery. Materials and Methods Cells, transfections, and reagents Northern blot, run-on assay, and RNA-binding assay All cell types are human. K562 is a hematopoietic stem cell–like line. THP1 For Northern analysis, total RNA from K562 was isolated with TRIzol is an immature monocytic leukemia line. MonoMac6 cells are a more reagent (Invitrogen). A 674-bp 32P-labeled sense or antisense RNA probe highly differentiated monocytic cell line (59). Each was maintained in was generated by in vitro transcription with the MAXIscript kit (Invi- RPMI 1640 with 10% cosmic calf serum (Fisher Scientific, Pittsburgh, trogen). Hybridization was performed using QuickHyb (Agilent, La Jolla, PA). Primary monocytes were obtained from normal human donors and CA), following the manufacturer9s instructions. purified by elutriation at the Penn Center for AIDS Research and then The modified run-on assay was performed, as described (64). Nuclei ∼ further purified by adherence. They were 90% pure, as defined by CD14 were isolated, and transcription was allowed to proceed in the presence of expression. Transfection of cells was performed by electroporation with biotin-16-UTP (Roche, Indianapolis, IN). The nascent
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