Schizophrenia is a complex genetic disorder, the non-Mendelian features of which are likely complicated by epigenetic factors yet to be elucidated. Here, we performed RNA sequencing of peripheral blood RNA from monozygotic twins discordant for schizophrenia, and identified a schizophrenia-associated upregulated long noncoding RNA (lncRNA, AC006129.1) that participates in the inflammatory response by enhancing SOCS3 and CASP1 expression in schizophrenia patients and further validated this finding in AC006129.1-overexpressing mice showing schizophrenia-related abnormal behaviors. We find that AC006129.1 binds to the promoter region of the transcriptional repressor Capicua (CIC), facilitates the interactions of DNA methyltransferases with the CIC promoter, and promotes DNA methylation-mediated CIC downregulation, thereby ameliorating CIC-induced SOCS3 and CASP1 repression. Derepression of SOCS3 enhances the anti-inflammatory response by inhibiting JAK/STAT-signaling activation. Our findings reveal an epigenetic mechanism with etiological and therapeutic implications for schizophrenia.
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Millan MJ, Andrieux A, Bartzokis G, Cadenhead K, Dazzan P, Fusar-Poli P, et al. Altering the course of schizophrenia: progress and perspectives. Nat Rev Drug Discov. 2016;15:485–515.
Van OsJ, Kenis G, Rutten BP. The environment and schizophrenia. Nature. 2010;468:203–12.
Khandaker GM, Cousins L, Deakin J, Lennox BR, Yolken R, Jones PB. Inflammation and immunity in schizophrenia: implications for pathophysiology and treatment. Lancet Psychiatry. 2015;2:258–70.
Feigenson KA, Kusnecov AW, Silverstein SM. Inflammation and the two-hit hypothesis of schizophrenia. Neurosci Biobehav Rev. 2014;38:72–93.
Rinn JL, Chang HY. Genome regulation by long noncoding RNAs. Annu Rev Biochem. 2012;81:145–66.
Lin H, Jiang M, Liu L, Yang Z, Ma Z, Liu S, et al. The long noncoding RNA Lnczc3h7a promotes a TRIM25-mediated RIG-I antiviral innate immune response. Nat Immunol. 2019;20:812–23.
Briggs JA, Wolvetang EJ, Mattick JS, Rinn JL, Barry G. Mechanisms of long non-coding RNAs in mammalian nervous system development, plasticity, disease, and evolution. Neuron. 2015;88:861–77.
Mathy NW, Chen XM. Long non-coding RNAs (lncRNAs) and their transcriptional control of inflammatory responses. J Biol Chem. 2017;292:12375–82.
Na KS, Jung HY, Kim YK. The role of pro-inflammatory cytokines in the neuroinflammation and neurogenesis of schizophrenia. Prog neuro-Psychopharmacol Biol psychiatry. 2014;48:277–86.
The Network Pathway Analysis Subgroup of the Psychiatric Genomics C. Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways. Nat Neurosci. 2015;18:199–209.
Richard MD, Brahm NC. Schizophrenia and the immune system: pathophysiology, prevention, and treatment. Am J Health Syst Pharm. 2012;69:757–66.
Drexhage RC, Hoogenboezem TA, Cohen D, Versnel MA, Nolen WA, van Beveren NJ, et al. An activated set point of T-cell and monocyte inflammatory networks in recent-onset schizophrenia patients involves both pro- and anti-inflammatory forces. Int J Neuropsychopharmacol. 2011;14:746–55.
Jones KA, Thomsen C. The role of the innate immune system in psychiatric disorders. Mol Cell Neurosci. 2013;53:52–62.
Lawrence T, Natoli G. Transcriptional regulation of macrophage polarization: enabling diversity with identity. Nat Rev Immunol. 2011;11:750–61.
Cianciulli A, Calvello R, Porro C, Trotta T, Panaro MA. Understanding the role of SOCS signaling in neurodegenerative diseases: current and emerging concepts. Cytokine Growth Factor Rev. 2017;37:67–79.
Qin H, Wilson CA, Roberts KL, Baker BJ, Zhao X, Benveniste EN. IL-10 inhibits lipopolysaccharide-induced CD40 gene expression through induction of suppressor of cytokine signaling-3. J Immunol. 2006;177:7761–71.
Baker BJ, Akhtar LN, Benveniste EN. SOCS1 and SOCS3 in the control of CNS immunity. Trends Immunol. 2009;30:392–400.
Chew CL, Conos SA, Unal B, Tergaonkar V. Noncoding RNAs: master regulators of inflammatory signaling. Trends Mol Med. 2018;24:66–84.
Du M, Yuan L, Tan X, Huang D, Wang X, Zheng Z, et al. The LPS-inducible lncRNA Mirt2 is a negative regulator of inflammation. Nat Commun. 2017;8:2049.
Li H, Li Q, Guo T, He W, Dong C, Wang Y. LncRNA CRNDE triggers inflammation through the TLR3-NF-kappaB-cytokine signaling pathway. Tumour Biol. 2017;39:1010428317703821.
Liu S, Wang Z, Chen D, Zhang B, Tian RR, Wu J, et al. Annotation and cluster analysis of spatiotemporal- and sex-related lncRNA expression in rhesus macaque brain. Genome Res. 2017;27:1608–20.
Schmitz KM, Mayer C, Postepska A, Grummt I. Interaction of noncoding RNA with the rDNA promoter mediates recruitment of DNMT3b and silencing of rRNA genes. Genes Dev. 2010;24:2264–9.
Deng Y, Luan S, Zhang Q, Xiao Y. Long noncoding RNA THRIL contributes in lipopolysaccharide-induced HK-2 cells injury by sponging miR-34a. J Cell Biochem. 2018;120:1–13.
Barry G, Briggs JA, Vanichkina DP, Poth EM, Beveridge NJ, Ratnu VS, et al. The long non-coding RNA Gomafu is acutely regulated in response to neuronal activation and involved in schizophrenia-associated alternative splicing. Mol Psychiatry. 2014;19:486–94.
Zhuo C, Hou W, Hu L, Lin C, Chen C, Lin X. Genomic editing of non-coding RNA genes with CRISPR/Cas9 ushers in a potential novel approach to study and treat schizophrenia. Front Mol Neurosci. 2017;10:28.
Tian T, Wei Z, Chang X, Liu Y, Gur RE, Sleiman PMA, et al. The long noncoding RNA landscape in amygdala tissues from schizophrenia patients. EBioMedicine. 2018;34:171–81.
Katsel P, Roussos P, Fam P, Khan S, Tan W, Hirose T, et al. The expression of long noncoding RNA NEAT1 is reduced in schizophrenia and modulates oligodendrocytes transcription. NPJ Schizophr. 2019;5:3.
Gandal MJ, Zhang P, Hadjimichael E, Walker RL, Chen C, Liu S, et al. Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder. Science. 2018;362:eaat8127.
Robinson MD, McCarthy DJ, Smyth GK. edgeR: a bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics. 2010;26:139–40.
Langfelder P, Horvath S. WGCNA: an R package for weighted correlation network analysis. BMC Bioinforma. 2008;9:559.
Lin J, Wen Y, He S, Yang X, Zhang H, Zhu H. Pipelines for cross-species and genome-wide prediction of long noncoding RNA binding. Nat Protoc. 2019;14:795–818.
Wang J, Duncan D, Shi Z, Zhang B. WEB-based GEne SeT AnaLysis Toolkit (WebGestalt): update 2013. Nucleic Acids Res. 2013;41:W77–83.
Fromer M, Roussos P, Sieberts SK, Johnson JS, Kavanagh DH, Perumal TM, et al. Gene expression elucidates functional impact of polygenic risk for schizophrenia. Nat Neurosci. 2016;19:1442–53.
Liu Y, Chang X, Hahn CG, Gur RE, Sleiman PAM, Hakonarson H. Non-coding RNA dysregulation in the amygdala region of schizophrenia patients contributes to the pathogenesis of the disease. Transl Psychiatry. 2018;8:44.
Fillman SG, Cloonan N, Catts VS, Miller LC, Wong J, McCrossin T, et al. Increased inflammatory markers identified in the dorsolateral prefrontal cortex of individuals with schizophrenia. Mol Psychiatry. 2013;18:206–14.
Wu Y, Yao YG, Luo XJ. SZDB: a database for schizophrenia genetic research. Schizophr Bull. 2017;43:459–71.
Duan J, Goring HHH, Sanders AR, Moy W, Freda J, Drigalenko EI, et al. Transcriptomic signatures of schizophrenia revealed by dopamine perturbation in an ex vivo model. Transl Psychiatry. 2018;8:158.
Sanders AR, Drigalenko EI, Duan J, Moy W, Freda J, Goring HHH, et al. Transcriptome sequencing study implicates immune-related genes differentially expressed in schizophrenia: new data and a meta-analysis. Transl Psychiatry. 2017;7:e1093.
GTEx Consortium, Laboratory, Data Analysis & Coordinating Center (LDACC)—Analysis Working Group, Statistical Methods groups—Analysis Working Group, Enhancing GTEx (eGTEx) groups, NIH Common Fund, et al. Genetic effects on gene expression across human tissues. Nature. 2017;550:204–13.
Wang H, Liu F, Chen W, Sun X, Cui W, Dong Z, et al. Genetic recovery of ErbB4 in adulthood partially restores brain functions in null mice. Proc Natl Acad Sci USA. 2018;115:13105–10.
Tang H, Hammack C, Ogden SC, Wen Z, Qian X, Li Y, et al. Zika virus infects human cortical neural progenitors and attenuates their growth. Cell Stem Cell. 2016;18:587–90.
Wen Z, Nguyen HN, Guo Z, Lalli MA, Wang X, Su Y, et al. Synaptic dysregulation in a human iPS cell model of mental disorders. Nature. 2014;515:414–8.
Xu M, Lee EM, Wen Z, Cheng Y, Huang WK, Qian X, et al. Identification of small-molecule inhibitors of Zika virus infection and induced neural cell death via a drug repurposing screen. Nat Med. 2016;22:1101–7.
Wang X, Ye F, Wen Z, Guo Z, Yu C, Huang WK et al. Structural interaction between DISC1 and ATF4 underlying transcriptional and synaptic dysregulation in an iPSC model of mental disorders. Mol Psychiatry. 2019. https://doi.org/10.1038/s41380-019-0485-2.
Bentea E, Depasquale EAK, O’Donovan SM, Sullivan CR, Simmons M, Meador-Woodruff JH, et al. Kinase network dysregulation in a human induced pluripotent stem cell model of DISC1 schizophrenia. Mol omics. 2019;15:173–88.
McQuade A, Coburn M, Tu CH, Hasselmann J, Davtyan H, Blurton-Jones M. Development and validation of a simplified method to generate human microglia from pluripotent stem cells. Mol Neurodegener. 2018;13:67.
Kim E, Lu HC, Zoghbi HY, Song JJ. Structural basis of protein complex formation and reconfiguration by polyglutamine disease protein Ataxin-1 and Capicua. Genes Dev. 2013;27:590–5.
Orefice LL, Zimmerman AL, Chirila AM, Sleboda SJ, Head JP, Ginty DD. Peripheral mechanosensory neuron dysfunction underlies tactile and behavioral deficits in mouse models of ASDs. Cell. 2016;166:299–313.
Zhao C, Xu Z, Chen J, Yu Z, Tong KL, Lo WS, et al. Two isoforms of GABA(A) receptor beta2 subunit with different electrophysiological properties: Differential expression and genotypical correlations in schizophrenia. Mol Psychiatry. 2006;11:1092–105.
Alkelai A, Lupoli S, Greenbaum L, Kohn Y, Kanyas-Sarner K, Ben-Asher E, et al. DOCK4 and CEACAM21 as novel schizophrenia candidate genes in the Jewish population. Int J Neuropsychopharmacol. 2012;15:459–69.
Fang S, Zhang L, Guo J, Niu Y, Wu Y, Li H, et al. NONCODEV5: a comprehensive annotation database for long non-coding RNAs. Nucleic Acids Res. 2018;46:D308–D314.
Mas-Ponte D, Carlevaro-Fita J, Palumbo E, Hermoso Pulido T, Guigo R, Johnson R. LncATLAS database for subcellular localization of long noncoding RNAs. RNA. 2017;23:1080–7.
Wong ML, Inserra A, Lewis MD, Mastronardi CA, Leong L, Choo J, et al. Inflammasome signaling affects anxiety- and depressive-like behavior and gut microbiome composition. Mol Psychiatry. 2016;21:797–805.
Calcia MA, Bonsall DR, Bloomfield PS, Selvaraj S, Barichello T, Howes OD. Stress and neuroinflammation: a systematic review of the effects of stress on microglia and the implications for mental illness. Psychopharmacology. 2016;233:1637–50.
Lee CJ, Chan WI, Cheung M, Cheng YC, Appleby VJ, Orme AT, et al. CIC, a member of a novel subfamily of the HMG-box superfamily, is transiently expressed in developing granule neurons. Brain Res Mol Brain Res. 2002;106:151–6.
Franzen O, Gan LM, Bjorkegren JLM. PanglaoDB: a web server for exploration of mouse and human single-cell RNA sequencing data. Database. 2019;2019:baz046.
Zhang Y, Chen K, Sloan SA, Bennett ML, Scholze AR, O’Keeffe S, et al. An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J Neurosci. 2014;34:11929–47.
Fores M, Simon-Carrasco L, Ajuria L, Samper N, Gonzalez-Crespo S, Drosten M, et al. A new mode of DNA binding distinguishes Capicua from other HMG-box factors and explains its mutation patterns in cancer. PLoS Genet. 2017;13:e1006622.
Nakagawa Y, Chiba K. Involvement of Neuroinflammation during Brain Development in Social Cognitive Deficits in Autism Spectrum Disorder and Schizophrenia. J Pharm Exp Ther. 2016;358:504–15.
Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014;511:421–7.
Yuan N, Chen Y, Xia Y, Dai J, Liu C. Inflammation-related biomarkers in major psychiatric disorders: a cross-disorder assessment of reproducibility and specificity in 43 meta-analyses. Transl Psychiatry. 2019;9:233.
Lu HC, Tan Q, Rousseaux MW, Wang W, Kim JY, Richman R, et al. Disruption of the ATXN1-CIC complex causes a spectrum of neurobehavioral phenotypes in mice and humans. Nat Genet. 2017;49:527–36.
Kim E, Park S, Choi N, Lee J, Yoe J, Kim S, et al. Deficiency of Capicua disrupts bile acid homeostasis. Sci Rep. 2015;5:8272.
Qin H, Yeh WI, De Sarno P, Holdbrooks AT, Liu Y, Muldowney MT, et al. Signal transducer and activator of transcription-3/suppressor of cytokine signaling-3 (STAT3/SOCS3) axis in myeloid cells regulates neuroinflammation. Proc Natl Acad Sci USA. 2012;109:5004–9.
Kirkpatrick B, Miller BJ. Inflammation and schizophrenia. Schizophr Bull. 2013;39:1174–9.
We are grateful to Dr Huda Y. Zoghbi, and Ji-Joon Song for the gift of the pUAST-CIC plasmid. We thank the National Natural Science Foundation of China [grant number 81871049, 81671333], the Guangdong Science and Technology Foundation [grant number 2019B030316032], and Guangzhou Science Technology and Innovation Commission [grant number 201804010259, 201807010064] for providing financial supports. We thank the individuals for their willingness to participate in this study. We thank Center for Applied Genomics, the Children’s Hospital of Philadelphia for sharing postmortem brain RNA-seq dataset (https://www.ncbi.nlm.nih.gov/sra/?term=SRP102186). We also thank the NIMH Repository and Genomics Resources approve our request for data generated by the CMC. The requested data were generated as part of the CMC supported by funding from Takeda Pharmaceuticals Company Limited, F. Hoffman-La Roche Ltd., and NIH grants R01MH085542, R01MH093725, P50MH066392, P50MH080405, R01MH097276, RO1-MH-075916, P50M096891, P50MH084053S1, R37MH057881 and R37MH057881S1, HHSN271201300031C, AG02219, AG05138, and MH06692. Brain tissue for the study was obtained from the following brain bank collections: the Mount Sinai NIH Brain and Tissue Repository, the University of Pennsylvania Alzheimer’s Disease Core Center, the University of Pittsburgh NeuroBioBank and Brain and Tissue Repositories, and the NIMH Human Brain Collection Core. CMC Leadership: Pamela Sklar, Joseph Buxbaum (Icahn School of Medicine at Mount Sinai), Bernie Devlin, David Lewis (University of Pittsburgh), Raquel Gur, Chang-Gyu Hahn (University of Pennsylvania), Keisuke Hirai, Hiroyoshi Toyoshiba (Takeda Pharmaceuticals Company Limited), Enrico Domenici, Laurent Essioux (F. Hoffman-La Roche Ltd), Lara Mangravite, Mette Peters (Sage Bionetworks), Thomas Lehner, Barbara Lipska (NIMH).
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Ni, C., Jiang, W., Wang, Z. et al. LncRNA-AC006129.1 reactivates a SOCS3-mediated anti-inflammatory response through DNA methylation-mediated CIC downregulation in schizophrenia. Mol Psychiatry (2020). https://doi.org/10.1038/s41380-020-0662-3
Experimental & Molecular Medicine (2020)