LncRNA-AC006129.1 reactivates a SOCS3-mediated anti-inflammatory response through DNA methylation-mediated CIC downregulation in schizophrenia

Ni, Chaoying; Jiang, Wei; Wang, Zhongju; Wang, Zhuo; Zhang, Jian; Zheng, Xianzhen; Liu, Zelin; Ou, Haiyan; Jiang, Tian; Liang, Wenquan; Wu, Fengchun; Li, Qiyang; Hou, Yu; Yang, Qiong; Guo, Bo; Liu, Sihan; Li, Shuyun; Li, Shufen; Yang, Ence; Zhu, Xinhong; Huang, Xingbing; Wen, Zhexing; Zhao, Cunyou

doi:10.1038/s41380-020-0662-3

“…The levels of CIC and lncRNA-AC006129.1, of which genomic locus is close to CIC in chromosome 19, were significantly decreased and increased in samples from schizophrenia patients, respectively 62 . AC006129.1 transgenic mice exhibited social interaction deficits, spatial working memory impairments, and sensorimotor gating disruption accompanied by upregulation of inflammatory response genes, including SOCS3 and CASP1, which are CIC target genes 62 . The overexpression of AC006129.1 downregulated CIC levels in both mouse and human cells 62 , suggesting that this lncRNA-mediated transcriptional repression of CIC expression might be conserved in mammals.…”

Section: Regulation Of Cicmentioning

confidence: 96%

“…Long noncoding RNA (lncRNA)-mediated regulation of CIC expression has been reported 62 . The levels of CIC and lncRNA-AC006129.1, of which genomic locus is close to CIC in chromosome 19, were significantly decreased and increased in samples from schizophrenia patients, respectively 62 .…”

Section: Regulation Of Cicmentioning

confidence: 99%

“…Long noncoding RNA (lncRNA)-mediated regulation of CIC expression has been reported 62 . The levels of CIC and lncRNA-AC006129.1, of which genomic locus is close to CIC in chromosome 19, were significantly decreased and increased in samples from schizophrenia patients, respectively 62 . AC006129.1 transgenic mice exhibited social interaction deficits, spatial working memory impairments, and sensorimotor gating disruption accompanied by upregulation of inflammatory response genes, including SOCS3 and CASP1, which are CIC target genes 62 .…”

Section: Regulation Of Cicmentioning

confidence: 99%

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Regulation and function of capicua in mammals

Lee

¹

2020

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Capicua (CIC) is an evolutionarily conserved transcription factor. CIC contains a high-mobility group (HMG) box that recognizes specific DNA sequences to regulate the expression of various target genes. CIC was originally identified in Drosophila melanogaster as a transcriptional repressor that suppresses the receptor tyrosine kinase signaling pathway. This molecule controls normal organ growth and tissue patterning as well as embryogenesis in Drosophila. Recent studies have also demonstrated its extensive functions in mammals. For example, CIC regulates several developmental and physiological processes, including lung development, abdominal wall closure during embryogenesis, brain development and function, neural stem cell homeostasis, T cell differentiation, and enterohepatic circulation of bile acids. CIC is also associated with the progression of various types of cancer and neurodegeneration in spinocerebellar ataxia type-1, systemic autoimmunity, and liver injury. In this review, I provide a broad overview of our current understanding of the regulation and functions of CIC in mammals and discuss future research directions.

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“…Further experiments showed that AC006129.1 interacts with the promoter region of the transcriptional repressor Capicua (CIC) to enhance the interactions of DNA methyltransferases with its promoter and decrease CIC expression, thus reversing CIC-associated SOCS3 and CASP1 suppression. Activation of SOCS3 increases the anti-inflammatory reactions by obstructing JAK/STAT pathway (27). Table 2 exhibits the list of up-regulated lncRNAs in schizophrenia.…”

Section: Lncrna Profile In Peripheral Bloodmentioning

confidence: 99%

A Review on the Expression Pattern of Non-coding RNAs in Patients With Schizophrenia: With a Special Focus on Peripheral Blood as a Source of Expression Analysis

Ghafouri‐Fard

¹

,

Eghtedarian

²

,

Taheri

³

et al. 2021

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Schizophrenia is a destructive neuropsychiatric disease with a median prevalence of 4.0 per 1,000 during the whole life. Genome-wide association studies have shown the role of copy number variants (generally deletions) and certain alleles of common single nucleotide polymorphisms in the pathogenesis of schizophrenia. This disorder predominantly follows the polygenic inheritance model. Schizophrenia has also been linked with various alterations in the transcript and protein content of the brain tissue. Recent studies indicate that alterations in non-coding RNAs (ncRNAs) signature underlie a proportion of this dysregulation. High throughput microarray investigations have demonstrated momentous alterations in the expression of long non-coding RNAs (lncRNA) and microRNAs (miRNAs) in the circulation or post-mortem brain tissues of patients with schizophrenia compared with control samples. While Gomafu, PINT, GAS5, TCONS_l2_00021339, IFNG-AS1, FAS-AS1, PVT1, and TUG1 are among down-regulated lncRNAs in schizophrenia, MEG3, THRIL, HOXA-AS2, Linc-ROR, SPRY4-IT1, UCA1, and MALAT1 have been up-regulated in these patients. Moreover, several miRNAs, such as miR-30e, miR-130b, hsa-miR-130b, miR-193a-3p, hsa-miR-193a-3p, hsa-miR-181b, hsa-miR-34a, hsa-miR-346, and hsa-miR-7 have been shown to be dysregulated in blood or brain samples of patients with schizophrenia. Dysregulation of these transcripts in schizophrenia not only provides insight into the pathogenic processes of this disorder, it also suggests these transcripts could serve as diagnostic markers for schizophrenia. In the present paper, we explore the changes in the expression of miRNAs and lncRNAs in patients with schizophrenia.

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“…Increasing studies had proposed that lncRNAs are implicated in various physiological and pathological processes including inflammatory response [ 13 , 14 ]. For example, AC006129.1 reactivates a SOCS3-induced anti-inflammatory response via DNA methylation-induced CIC downregulation in schizophrenia [ 15 ]. Moreover, Arid2-IR regulates inflammatory response by targeting the TGF-b/smad signaling pathway, which may serve as a novel therapeutic target for the improvement of renal inflammation [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

Suppression of lncRNA MALAT1 Reduces LPS- or IL-17A-Induced Inflammatory Response in Human Middle Ear Epithelial Cells via the NF-κB Signaling Pathway

Yang

¹

,

Zhang

²

,

Lü

³

et al. 2021

BioMed Research International

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Otitis media (OM) is a common inflammatory disease of the middle ear cavity and mainly occurs in children. As a critical regulator of inflammation response, the nuclear factor kappa B (NF-κB) pathway has been found to play an essential role in the pathogenesis of various human diseases. The aim of this study was to explore the potential mechanism under the inflammatory response of human middle ear epithelial cells (HMEECs). We established in vitro models of OM by treating HMEECs with lipopolysaccharide (LPS) or interleukin 17A (IL-17A). Enzyme-linked immunosorbent assay and western blot analysis were used to measure the inflammatory response of HMEECs under LPS or IL-17A stimulation. The results revealed that the concentrations of proinflammatory cytokines ( p < 0.001 ) and protein levels of mucin (MUC) (for MUC5AC, p = 0.002 , p = 0.004 ; for MUC8, p = 0.004 , p < 0.001 ) were significantly elevated by LPS or IL-17A stimulation in HMEECs. Moreover, we found that LPS or IL-17A treatment promoted the phosphorylation of IκBα (for p-IκBα, p = 0.018 , p = 0.002 ; for IκBα, p = 0.238 , p = 0.057 ) and the translocation of p65 from cytoplasm to nucleus in HMEECs (for nucleus p65, p = 0.01 ; for cytoplasm p65, p < 0.001 ). In addition, RT-qPCR analysis revealed that long noncoding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) was verified to be upregulated in LPS- or IL-17A-stimulated HMEECs ( p < 0.001 ). Western blot analysis and immunofluorescence staining assay revealed that that MALAT1 knockdown significantly suppressed the activation of the NF-κB pathway by reducing phosphorylated IκBα levels and inhibiting the nuclear translocation of p65 ( p < 0.001 ) in LPS- or IL-17A-stimulated HMEECs (for p-IκBα, p < 0.001 ; for IκBα, p = 0.242 , p = 0.647 ). Silence of MALAT1 decreased the proinflammatory cytokine production and MUC protein levels ( p < 0.001 ). Furthermore, rescue assays revealed that the increase of proinflammatory cytokine production (for TNF-α, p = 0.002 , p = 0.015 ; for IL-1β, p < 0.001 , p = 0.006 ; for IL-6, p = 0.002 , p < 0.001 ) and MUC protein levels (for MUC5AC, p = 0.001 , p < 0.001 ; for MUC8, p < 0.001 , p = 0.001 ) induced by MALAT1 overexpression was neutralized by 4-N-[2-(4-phenoxyphenyl) ethyl] quinazoline-4, 6-diamine (QNZ) treatment in LPS- or IL-17A-stimulated HMEECs. In conclusion, MALAT1 promotes inflammatory response in LPS- or IL-17A- stimulated HMEECs via the NF-κB signaling pathway, which may provide a potential novel insight for the treatment of OM.

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LncRNA-AC006129.1 reactivates a SOCS3-mediated anti-inflammatory response through DNA methylation-mediated CIC downregulation in schizophrenia

Cited by 26 publications

References 65 publications

Regulation and function of capicua in mammals

Regulation and function of capicua in mammals

A Review on the Expression Pattern of Non-coding RNAs in Patients With Schizophrenia: With a Special Focus on Peripheral Blood as a Source of Expression Analysis

Suppression of lncRNA MALAT1 Reduces LPS- or IL-17A-Induced Inflammatory Response in Human Middle Ear Epithelial Cells via the NF-κB Signaling Pathway

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