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

Abstract

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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Fig. 1: Association of AC006129.1 and its related genes with schizophrenia.
Fig. 2: AC006129.1-induced aberrant mouse behavior through the regulation of inflammatory response genes.
Fig. 3: AC006129.1 promoted DNA methylation-mediated CIC downregulation.
Fig. 4: Derepression of SOCS3 and CASP1 by AC006129.1-mediated CIC downregulation.
Fig. 5: Proposed model of the derepression of SOCS3 and CASP1 by AC006129.1-mediated CIC hypermethylation and downregulation.

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Acknowledgements

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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Conceived and designed the experiments: CN, WJ and CZ. Performed the experiments: CN, WJ, ZW, WL, QL, YH, BG and SL. Analyzed the data: CN, WJ, ZW, JZ, ZL, HO, SL, EY, XZ, ZW and CZ. Collected and diagnosed the control and patient subjects: XZ, TJ, FW, QY, SL and XH. Wrote the paper: CN, WJ, ZW and CZ.

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Correspondence to Cunyou Zhao.

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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

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