Center for Neurobehavioral Genetics, Semel Institute for Neuroscience & Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA; Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; UCLA Brain Research Institute, University of California, Los Angeles, Los Angeles, CA, USA.
Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; UCLA Brain Research Institute, University of California, Los Angeles, Los Angeles, CA, USA.
Neuron. 2022 Oct 19;110(20):3318-3338.e9. doi: 10.1016/j.neuron.2022.09.028.
Brain tissue transcriptomes may be organized into gene coexpression networks, but their underlying biological drivers remain incompletely understood. Here, we undertook a large-scale transcriptomic study using 508 wild-type mouse striatal tissue samples dissected exclusively in the afternoons to define 38 highly reproducible gene coexpression modules. We found that 13 and 11 modules are enriched in cell-type and molecular complex markers, respectively. Importantly, 18 modules are highly enriched in daily rhythmically expressed genes that peak or trough with distinct temporal kinetics, revealing the underlying biology of striatal diurnal gene networks. Moreover, the diurnal coexpression networks are a dominant feature of daytime transcriptomes in the mouse cortex. We next employed the striatal coexpression modules to decipher the striatal transcriptomic signatures from Huntington's disease models and heterozygous null mice for 52 genes, uncovering novel functions for Prkcq and Kdm4b in oligodendrocyte differentiation and bipolar disorder-associated Trank1 in regulating anxiety-like behaviors and nocturnal locomotion.
脑组织转录组可能被组织成基因共表达网络，但它们的潜在生物学驱动因素仍不完全清楚。在这里，我们使用 508 个野生型小鼠纹状体组织样本进行了大规模转录组研究，这些样本仅在下午进行解剖，以定义 38 个高度可重复的基因共表达模块。我们发现，13 个和 11 个模块分别富含细胞类型和分子复合物标记物。重要的是，18 个模块高度富集具有独特时间动力学的昼夜节律表达基因，揭示了纹状体昼夜基因网络的潜在生物学。此外，昼夜共表达网络是小鼠皮层白天转录组的主要特征。接下来，我们利用纹状体共表达模块来解析亨廷顿病模型和 52 个基因杂合缺失小鼠的纹状体转录组特征，揭示了 Prkcq 和 Kdm4b 在少突胶质细胞分化中的新功能，以及与双相情感障碍相关的 Trank1 在调节焦虑样行为和夜间运动中的作用。
