Cooperation of LIM domain-binding 2 (LDB2) with EGR in the pathogenesis of schizophrenia.
Cooperation of LIM domain-binding 2 (LDB2) with EGR in the pathogenesis of schizophrenia.
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DOI：
10.15252/emmm.202012574
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发表时间：
2021-04-09
影响因子：
11.1
通讯作者：
Yoshikawa T
中科院分区：
文献类型：
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作者：
Ohnishi T;Kiyama Y;Arima-Yoshida F;Kadota M;Ichikawa T;Yamada K;Watanabe A;Ohba H;Tanaka K;Nakaya A;Horiuchi Y;Iwayama Y;Toyoshima M;Ogawa I;Shimamoto-Mitsuyama C;Maekawa M;Balan S;Arai M;Miyashita M;Toriumi K;Nozaki Y;Kurokawa R;Suzuki K;Yoshikawa A;Toyota T;Hosoya T;Okuno H;Bito H;Itokawa M;Kuraku S;Manabe T;Yoshikawa T
具有大效应量的基因组缺陷有助于阐明精神障碍的未知病理结构。我们以前报道过一个精神分裂症患者，4号染色体和13号染色体之间的平衡易位，发现4号染色体内的断点位于LDB2基因附近。我们在这里表明，Ldb2敲除（KO）小鼠显示出与精神障碍相关的多种缺陷。特别是，Ldb2 KO小鼠在恐惧-条件反射范式中表现出缺陷。对杏仁核的分析表明，由直接早期基因Arc控制的突触活动失调与这种表型有关。我们发现LDB2与已知的转录因子形成蛋白复合物。一致地，ChIP‐seq分析表明，LDB2与人类神经球中大约10000个基因组位点结合。我们发现许多这些位点，包括ARC的启动子区域，都被EGR转录因子占据。我们之前的研究表明EGR家族基因与精神分裂症有关。总的来说，这些发现表明，由LDB2‐EGR轴控制的基因表达失调是精神疾病亚群发病机制的基础。LDB2基因被定位在一个精神分裂症患者的平衡染色体易位的断点上。本研究探讨了LDB2和“LDB2 - EGR轴”在精神障碍发病机制中的转录调控作用。
Genomic defects with large effect size can help elucidate unknown pathologic architecture of mental disorders. We previously reported on a patient with schizophrenia and a balanced translocation between chromosomes 4 and 13 and found that the breakpoint within chromosome 4 is located near the LDB2 gene. We show here that Ldb2 knockout (KO) mice displayed multiple deficits relevant to mental disorders. In particular, Ldb2 KO mice exhibited deficits in the fear‐conditioning paradigm. Analysis of the amygdala suggested that dysregulation of synaptic activities controlled by the immediate early gene Arc is involved in the phenotypes. We show that LDB2 forms protein complexes with known transcription factors. Consistently, ChIP‐seq analyses indicated that LDB2 binds to > 10,000 genomic sites in human neurospheres. We found that many of those sites, including the promoter region of ARC, are occupied by EGR transcription factors. Our previous study showed an association of the EGR family genes with schizophrenia. Collectively, the findings suggest that dysregulation in the gene expression controlled by the LDB2‐EGR axis underlies a pathogenesis of subset of mental disorders. The LDB2 gene is mapped at the breakpoint of a balanced chromosomal translocation seen in a patient with schizophrenia. This study investigates the role of LDB2 and transcriptional regulation exerted by the “LDB2‐EGR axis” in the pathogenesis of mental disorders.