Mental Health Research Center, Kashirskoe Sh., 34, Moscow 115522, Russia.
Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov Str. 32, Moscow 119991, Russia.
Int J Mol Sci. 2023 Oct 30;24(21):15746. doi: 10.3390/ijms242115746.
Schizophrenia (SZ) is a common psychiatric neurodevelopmental disorder with a complex genetic architecture. Genome-wide association studies indicate the involvement of several transcription factors, including ASCL1, in the pathogenesis of SZ. We aimed to identify ASCL1-dependent cellular and molecular mechanisms associated with SZ. We used Capture-C, CRISPR/Cas9 systems and RNA-seq analysis to confirm the involvement of ASCL1 in SZ-associated pathogenesis, establish a mutant SH-SY5Y line with a functional knockout (ASCL1-del) and elucidate differentially expressed genes that may underlie ASCL1-dependent pathogenic mechanisms. Capture-C confirmed the spatial interaction of the promoter with SZ-associated loci. Transcriptome analysis showed that regulation may be through a negative feedback mechanism. ASCL1 dysfunction affects the expression of genes associated with the pathogenesis of SZ, as well as bipolar and depressive disorders. Genes differentially expressed in ASCL1-del are involved in cell mitosis, neuronal projection, neuropeptide signaling, and the formation of intercellular contacts, including the synapse. After retinoic acid (RA)-induced differentiation, ASCL1 activity is restricted to a small subset of genes involved in neuroplasticity. These data suggest that ASCL1 dysfunction promotes SZ development predominantly before the onset of neuronal differentiation by slowing cell proliferation and impeding the formation of neuronal signatures.
精神分裂症（SZ）是一种常见的精神神经发育障碍，具有复杂的遗传结构。全基因组关联研究表明，包括 ASCL1 在内的几种转录因子参与了 SZ 的发病机制。我们旨在确定与 SZ 相关的 ASCL1 依赖性细胞和分子机制。我们使用 Capture-C、CRISPR/Cas9 系统和 RNA-seq 分析来确认 ASCL1 参与 SZ 相关发病机制，建立具有功能性缺失（ASCL1-del）的突变 SH-SY5Y 细胞系，并阐明可能是 ASCL1 依赖性致病机制基础的差异表达基因。Capture-C 证实了启动子与 SZ 相关基因座的空间相互作用。转录组分析表明，调控可能是通过负反馈机制进行的。ASCL1 功能障碍会影响与 SZ、双相情感障碍和抑郁症发病机制相关的基因表达。ASCL1-del 中差异表达的基因参与细胞有丝分裂、神经元投射、神经肽信号转导以及细胞间接触（包括突触）的形成。在视黄酸（RA）诱导分化后，ASCL1 的活性仅限于一组参与神经可塑性的少数基因。这些数据表明，ASCL1 功能障碍主要通过减缓细胞增殖和阻碍神经元特征的形成来促进 SZ 的发展，而不是在神经元分化之前。
