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A Long Noncoding RNA, Antisense IL-7, Promotes Inflammatory Gene Transcription Through Facilitating Histone Acetylation and Swit

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A Long Noncoding RNA, Antisense IL-7, Promotes Inflammatory Gene Transcription Through Facilitating Histone Acetylation and Swit Published August 5, 2019, doi:10.4049/jimmunol.1900256 The Journal of Immunology A Long Noncoding RNA, Antisense IL-7, Promotes Inflammatory Gene Transcription through Facilitating Histone Acetylation and Switch/Sucrose Nonfermentable Chromatin Remodeling Xu Liu,*,†,1 Yajing Lu,*,‡,1 Jie Zhu,* Mingjia Liu,* Minghong Xie,* Mengling Ye,* Mingxuan Li,* Shuhong Wang,* Zhenping Ming,* Qiang Tong,x Feng Liu,{ and Rui Zhou* Long noncoding RNAs are important regulators of gene expression in innate immune responses. Antisense IL-7 (IL-7–AS) is a newly discovered long noncoding RNA in human and mouse that has been reported to regulate the expression of IL-6. However, the potential function of IL-7–AS in innate immune system is not fully understood. In this study, we found that the expression of IL-7–AS is primarily dependent on the NF-kB and MAPK signaling pathways in macrophages and intestinal epithelial cells. Functionally, IL-7–AS promotes the expression of several inflammatory genes, including CCL2, CCL5, CCL7, and IL-6, in cells in response to LPS. Specifically, IL-7–AS physically interacts with p300 to regulate histone acetylation levels around the promoter regions of these gene loci. Moreover, IL-7–AS and p300 complex modulate the assembly of SWI/SNF complex to the promoters. IL-7–AS regulates chemotaxis activity of monocytes to intestine epithelial cells with involvement of CCL2. Therefore, our data indicate a new promoting role for NF-kB/MAPK-responsive IL-7–AS in the transcriptional regulation of inflammatory genes in the innate immune system although modulation of histone acetylation around the promoters of related genes. The Journal of Immunology, 2019, 203: 000–000. he innate immune system provides immediate defense and cause chronic inflammatory diseases, even cancer (5). Hence, against invading pathogens through induction of an in- the expression of inflammatory genes is tightly regulated to or- T flammatory response (1). Epithelial cells and macrophages chestrate the development of complex gene expression programs, have been recognized as important players in innate host defense including several waves of inflammatory gene transcription (2). These cells are equipped with several defense mechanisms to broadly categorized as the early primary genes (e.g., TNF-a, guard against infection by pathogens. They express a variety of CXCL2,andIL-8) and late inflammatory genes (e.g., CCL5, by guest on September 30, 2021. Copyright 2019 Pageant Media Ltd. pathogen pattern recognition receptors, such as the TLRs, which CCL2, IL-6, and IL-12b) (6). Studies demonstrated that chromatin recognize pathogens or pathogen-associated molecular patterns (3). remodeling contributes to the transcription of inflammatory genes, Upon specific pathogen recognition, these receptors recruit adaptor especially the late inflammatory genes (7). Chromatin remodeling proteins and activate downstream signaling cascades, including involves the dynamic modification of chromatin architecture to NF-ĸB and MAPKs, to regulate the transcription of genes involved facilitate access of condensed genomic DNA to the transcriptional in antimicrobial defense, cell migration, and regulation of adaptive machinery to control gene expression, which is carried out by immunity. Cytokines and chemokines produced by cells of the covalent histone modifications and ATP-dependent chromatin innate immune system mediate the inflammatory response (4). remodeling complexes, such as the switch/sucrose nonfermentable https://www.jimmunol.org However, excessive inflammation can exacerbate tissue damage (SWI/SNF) complex (8). *Hubei Province Key Laboratory of Allergy and Immunology, School of Basic X.L., Y.L., and R.Z. conceived the experiments and wrote the manuscript. J.Z., M. Liu, Medical Sciences, Wuhan University, Wuhan 430071, Hubei, People’s Republic of and M.X. performed real-time PCR experiments, M.Y. performed the RNA pull-down China; †Department of Biochemistry and Molecular Biology, Medical College, Hubei experiment, and M. Li and S.W. performed the luciferase assay experiment. Z.M., Q.T., Minzu University, Enshi 445000, Hubei, People’s Republic of China; ‡Department of and F.L. analyzed the data. Endocrinology, Institute of Geriatric Medicine, Liyuan Hospital, Tongji Medical Downloaded from Address correspondence and reprint requests to Dr. Rui Zhou, School of Basic College, Huazhong University of Science and Technology, Wuhan 430077, Hubei, x Medical Sciences, Wuhan University, 185 Donghu Road, Wuhan 430071, Hubei, People’s Republic of China; Department of Gastrointestinal Surgery Section, People’s Republic of China. E-mail address: [email protected] Renmin Hospital of Wuhan University, Wuhan 430060, Hubei, People’s Republic of China; and {School of Computer Sciences, Wuhan University, Wuhan 430072, The online version of this article contains supplemental material. Hubei, People’s Republic of China Abbreviations used in this article: CBP, CREB protein; ChIP, chromatin immunopre- 1Contributed equally to this work. cipitation; H3K9Ac, H3K9 acetylation; H3K14Ac, H3K14 acetylation; H3K4me3, H3K4 trimethylation; IL-7–AS, antisense IL-7; lnc-FAM164A, long noncoding ORCIDs: 0000-0001-8361-6510 (X.L.); 0000-0002-0179-9681 (Q.T.); 0000-0002- FAM164A; lncRNA, long noncoding RNA; m–IL-7–AS, mouse IL-7–AS; PCAF, 9927-5236 (R.Z.). p300/CBP-associated factor; PMPM, primary mouse peritoneal macrophage; RIP, Received for publication February 28, 2019. Accepted for publication July 8, 2019. RNA immunoprecipitation; siRNA, small interfering RNA; SWI/SNF, switch/sucrose nonfermentable. This work was supported by National Natural Science Foundation of China Grants 81771702, 81373132, and 31300744 (all to R.Z.), 81172186 (to Q.T.), and 61572368 Ó (to F.L.), the Specialized Research Fund for the Doctoral Program of Higher Copyright 2019 by The American Association of Immunologists, Inc. 0022-1767/19/$37.50 Education of China (Grant 20130141120011 to R.Z.), and Fundamental Research Funds for the Central Universities (Grant 2042018kf0249 to R.Z.). www.jimmunol.org/cgi/doi/10.4049/jimmunol.1900256 2 IL-7–AS MODULATES INFLAMMATORY RESPONSES Long noncoding RNAs (lncRNAs) are usually classified by their weight) (100 ng/ml, TLR3 agonist) were purchased from InvivoGen relative position to protein-coding genes and include the intergenic (San Diego, CA). SC-514 (100 mM; Sigma-Aldrich), a potent IKK-2 in- k lncRNAs, antisense, and pseudogenes. lncRNAs are emerging hibitor, was used to inhibit NF- B activation. The MAPK/MEK inhibitors, PD98059, SB203580, and SP600125, were obtained from Sigma-Aldrich. as major regulators of chromatin remodeling, transcription, and Cells were pretreated with SC-514 (100 mM) or a mixture of MAPK in- posttranscriptional regulation of gene expression in the innate hibitors (50 mM of PD98059, 10 mM of SB203580, and 20 mM of immune system (9). Dysregulation of lncRNAs has been associ- SP600125) for 1 h prior to LPS stimulation (16). C646, a histone acetyl- ated with various infectious diseases, inflammatory diseases, and transferase p300 inhibitor, was purchased from Sigma-Aldrich. Cells were pretreated with C646 (10 mM) for 12 h prior to LPS stimulation to in- tumorigenesis (10, 11). lncRNAs can be induced in innate immune hibit the activation of acetyltransferases (17). SC-514, C646, and MAPK cells and act as key regulators of the inflammatory response, es- inhibitors at the concentration used in these experiments showed no pecially to fine-tune the expression of inflammatory genes. Several cytotoxic effects on SW480, U937, and RAW264.7 cells. lncRNAs have been reported to be differentially expressed in in- Real-time PCR and RACE PCR nate immune cells after stimulation by ligands for TLR4 and TLR2. lncRNA-Cox2, one of the most highly induced lncRNAs in For quantitative analysis of mRNA and lncRNA expression, compara- tive real-time PCR was performed using SYBR Green PCR Master Mix murine macrophage, has been shown to regulate the transcrip- (Applied Biosystems, Carlsbad, CA) according to previous studies (14). tion of late primary response genes through modulating SWI/SNF- The results were analyzed by using the comparative cycle threshohld (DD associated chromatin remodeling (12). However, .95% of lncRNAs cycle threshold) method; Gapdh was used as an internal control for all the appear to show little evolutionary sequence conservation (13). human genes and b-actin as the internal control for all the mouse genes. Whereas most studies focused on immune-related lncRNAs in The primers for real-time PCR are listed in Supplemental Table I. The 59- and 39-RACE PCR was used to identify the 59 and 39 end of IL-7–AS mouse models, several lncRNAs have shown conservation of variants to localize the transcriptional start and stop sites by the SMART their functionality across species. For example, FIRRE has been RACE cDNA Amplification Kit (Clontech Laboratories, Mountain View, reported to regulate the expression of several inflammatory genes CA). The primers for RACE PCR analysis are listed in Supplemental via posttranscriptional mechanism through interacting with hnRNPU Table I. in both human and mouse cells (14). Nevertheless, the potential Small interfering RNAs and plasmids functions of these conserved lncRNAs in regulation of inflammatory For plasmid constructs, the full-length sequence of human IL-7–AS-V1 was responses in both human and mouse are largely unexplored. amplified using the primers depicted in Supplemental Table I. PCR Antisense IL-7 (IL-7–AS) [located antisense to IL-7 gene; ac- products were
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