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

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LncRNA-AC006129.1 reactivates a SOCS3-mediated anti-inflammatory response through DNA methylation-mediated CIC downregulation in schizophrenia.
Molecular Psychiatry ( IF 9.6 ) Pub Date : 2020-02-03 , DOI: 10.1038/s41380-020-0662-3
Chaoying Ni _{1,

2} , Wei Jiang _{1,

2} , Zhongju Wang _{1,

2} , Zhuo Wang _{2,

3} , Jian Zhang ₁ , Xianzhen Zheng ₄ , Zelin Liu ₅ , Haiyan Ou _{1,

2} , Tingyun Jiang ₆ , Wenquan Liang ₁ , Fengchun Wu ₇ , Qiyang Li _{1,

2} , Yu Hou ₁ , Qiong Yang ₇ , Bo Guo _{1,

2} , Sihan Liu ₈ , Shuyun Li ₇ , Shufen Li _{1,

2} , Ence Yang ₅ , Xin-Hong Zhu _{2,

3} , Xingbing Huang ₇ , Zhexing Wen ₉ , Cunyou Zhao _{1,

2}

Affiliation

Department of Medical Genetics, School of Basic Medical Sciences, Guangdong Technology and Engineering Research Center for Molecular Diagnostics of Human Genetic Diseases, and Guangdong Engineering and Technology Research Center for Genetic Testing, Southern Medical University, Guangzhou, China.
Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, and Guangdong Province Key Laboratory of Psychiatric Disorders, Southern Medical University, Guangzhou, Guangdong, China.
Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
Guangdong General Hospital, Guangdong Academy of Medical Science and Guangdong Mental Health Center, Guangzhou, China.
Institute of Systems Biomedicine, Department of Medical Bioinformatics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
The Third People's Hospital of Zhongshan, Zhongshan, Guangdong, China.
Department of Psychiatry, the Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou, Guangdong, China.
Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China.
Departments of Psychiatry and Behavior Sciences, Cell Biology, and Neurology, Emory University, Atlanta, GA, USA.

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.

中文翻译：

LncRNA-AC006129.1 在精神分裂症中通过 DNA 甲基化介导的 CIC 下调重新激活 SOCS3 介导的抗炎反应。

精神分裂症是一种复杂的遗传疾病，其非孟德尔特征可能因尚未阐明的表观遗传因素而复杂化。在这里，我们对来自精神分裂症不一致的同卵双胞胎的外周血 RNA 进行了 RNA 测序，并鉴定了一种与精神分裂症相关的上调长链非编码 RNA（lncRNA，AC006129.1），它通过增强精神分裂症患者的 SOCS3 和 CASP1 表达参与炎症反应，进一步在 AC006129.1 过表达小鼠中证实了这一发现，该小鼠表现出与精神分裂症相关的异常行为。我们发现 AC006129.1 与转录抑制因子 Capicua (CIC) 的启动子区域结合，促进 DNA 甲基转移酶与 CIC 启动子的相互作用，并促进 DNA 甲基化介导的 CIC 下调，从而改善 CIC 诱导的 SOCS3 和 CASP1 抑制。SOCS3 的去抑制通过抑制 JAK/STAT 信号激活来增强抗炎反应。我们的研究结果揭示了一种表观遗传机制，对精神分裂症具有病因学和治疗意义。

更新日期：2020-02-04

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