Department of Medical Genetics, Guangdong Technology and Engineering Research Center for Molecular Diagnostics of Human Genetic Diseases, and Guangdong Engineering and Technology Research Center for Genetic Testing, School of Basic Medical Sciences, and Guangdong Mental Health Center, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Science), 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, Guangdong-Hong Kong Joint Laboratory for Psychiatric Disorders, Guangdong Province Key Laboratory of Psychiatric Disorders, and Guangdong Basic Research Center of Excellence for Integrated Traditional and Western Medicine for Qingzhi Diseases, Southern Medical University, Guangzhou, Guangzhou, China.
BMC Med. 2024 Nov 18;22(1):543. doi: 10.1186/s12916-024-03725-0.
Bipolar disorder is a complex polygenic disorder that is characterized by recurrent episodes of depression and mania, the heterogeneity of which is likely complicated by epigenetic modifications that remain to be elucidated.
We performed transcriptomic analysis of peripheral blood RNA from monozygotic (MZ) twins discordant for bipolar disorder to identify disease-associated differentially expressed long noncoding RNAs (DE-lncRNAs), which were further validated in the PsychENCODE brain RNA-seq dataset. We then performed behavioral tests, electrophysiological assays, chromatin immunoprecipitation, and PCR to investigate the function of DE-lncRNAs in the mouse and cell models. Statistical analyses were performed using GraphPad Prism 9.0 or SPSS.
We identified a bipolar disorder-associated upregulated long non-coding RNA (lncRNA), AP1AR-DT. We observed that overexpression of AP1AR-DT in the mouse medial prefrontal cortex (mPFC) resulted in a reduction of both the total spine density and the spontaneous excitatory postsynaptic current (sEPSC) frequency of mPFC neurons as well as depressive and anxiety-like behaviors. A combination of the results of brain transcriptome analysis of AP1AR-DT overexpressing mice brains with the known genes associated with bipolar disorder revealed that NEGR1, which encodes neuronal growth regulator 1, is one of the AP1AR-DT targets and is reduced in vivo upon gain of AP1AR-DT in mice. We further demonstrated that overexpression of recombinant Negr1 in the mPFC neurons of AP1AR-DT mice ameliorates depressive and anxiety-like behaviors and normalizes the reduced excitatory synaptic transmission induced by the gain of AP1AR-DT. We finally identified that AP1AR-DT reduces NEGR1 expression by competing for the transcriptional activator NRF1 in the overlapping binding site of the NEGR1 promoter region.
The epigenetic and pathophysiological mechanism linking AP1AR-DT to the modulation of depressive and anxiety-like behaviors and excitatory synaptic function provides etiological implications for bipolar disorder.
双相情感障碍是一种复杂的多基因疾病，其特征是反复发作的抑郁和躁狂，其异质性可能因仍有待阐明的表观遗传修饰而变得复杂。
我们对双相情感障碍单卵双胞胎的外周血 RNA 进行了转录组分析，以鉴定与疾病相关的差异表达长非编码 RNA（DE-lncRNA），并在 PsychENCODE 大脑 RNA-seq 数据集进一步验证。然后，我们在小鼠和细胞模型中进行了行为测试、电生理测定、染色质免疫沉淀和 PCR，以研究 DE-lncRNA 的功能。统计分析使用 GraphPad Prism 9.0 或 SPSS 进行。
我们鉴定出一种与双相情感障碍相关的上调长非编码 RNA（lncRNA），即 AP1AR-DT。我们观察到，AP1AR-DT 在小鼠内侧前额叶皮层（mPFC）中的过表达导致 mPFC 神经元的总棘密度和自发性兴奋性突触后电流（sEPSC）频率降低，以及抑郁和焦虑样行为。AP1AR-DT 过表达小鼠大脑的脑转录组分析结果与已知与双相情感障碍相关的基因的组合结果表明，编码神经元生长调节剂 1 的 NEGR1 是 AP1AR-DT 的靶标之一，并且在小鼠中获得 AP1AR-DT 时体内减少。我们进一步证明，在 AP1AR-DT 小鼠的 mPFC 神经元中过表达重组 Negr1 可改善抑郁和焦虑样行为，并使由 AP1AR-DT 获得引起的兴奋性突触传递减少正常化。我们最终确定，AP1AR-DT 通过在 NEGR1 启动子区域的重叠结合位点与转录激活物 NRF1 竞争，从而降低 NEGR1 的表达。
AP1AR-DT 与调节抑郁和焦虑样行为及兴奋性突触功能的表观遗传和病理生理学机制为双相情感障碍提供了病因学意义。
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