加拿大麦吉尔大学Gustavo Turecki小组在研究中取得进展。他们发现了单核染色质可及性分析鉴定导致重度抑郁症的细胞类型和功能变异。2025年8月5日出版的《自然—遗传学》杂志发表了这项成果。

该团队通过将84个个体的背外侧前额叶皮层的20万多个细胞的单细胞染色质可及性与基因表达结合起来，研究了MDD与神经正常对照相比的基因调控机制。MDD相关的染色质可及性改变在以转录因子（TF）基序可及性和NR4A2结合为特征的深层兴奋性神经元中表现突出，NR4A2是一种对应激有反应的活性依赖的TF。同样的神经元富含MDD相关的遗传变异，破坏了与可能影响突触通讯的基因相关的TF结合位点。

此外，MDD患者的灰质小胶质细胞在已知调节免疫稳态的TF结合位点的可及性降低。最后，研究组通过基于序列的可及性预测、供体特异性基因型和基于细胞的分析，确定了MDD风险变异的基因调控作用。这些发现揭示了基因变异可能增加MDD风险的细胞类型和调控机制。

研究人员表示，与重度抑郁症（MDD）相关的遗传变异在调控基因组中富集。

附：英文原文

Title: Single-nucleus chromatin accessibility profiling identifies cell types and functional variants contributing to major depression

Author: Chawla, Anjali, Cakmakci, Doruk, Fiori, Laura M., Zang, Wenmin, Maitra, Malosree, Yang, Jennie, urawek, Dariusz, Frosi, Gabriella, Rahimian, Reza, Mitsuhashi, Haruka, Davoli, Maria Antonietta, Denniston, Ryan, Chen, Gary Gang, Yerko, Volodymyr, Mash, Deborah, Girdhar, Kiran, Akbarian, Schahram, Mechawar, Naguib, Suderman, Matthew, Li, Yue, Nagy, Corina, Turecki, Gustavo

Issue&Volume: 2025-08-05

Abstract: Genetic variants associated with major depressive disorder (MDD) are enriched in the regulatory genome. Here, we investigate gene-regulatory mechanisms underlying MDD compared to neurotypical controls by combining single-cell chromatin accessibility with gene expression in over 200,000 cells from the dorsolateral prefrontal cortex of 84 individuals. MDD-associated alterations in chromatin accessibility were prominent in deep-layer excitatory neurons characterized by transcription factor (TF) motif accessibility and binding of NR4A2, an activity-dependent TF reactive to stress. The same neurons were enriched for MDD-associated genetic variants, disrupting TF binding sites linked to genes that likely affect synaptic communication. Furthermore, a gray matter microglia cluster exhibited decreased accessibility in individuals with MDD at binding sites bound by TFs known to regulate immune homeostasis. Finally, we identified gene-regulatory effects of MDD-risk variants using sequence-based accessibility predictions, donor-specific genotypes and cell-based assays. These findings shed light on the cell types and regulatory mechanisms through which genetic variation may increase the risk of MDD.

DOI: 10.1038/s41588-025-02249-4

Source: https://www.nature.com/articles/s41588-025-02249-4