美国弗里德曼大脑研究所Panos Roussos小组近日取得一项新成果。经过不懈努力，他们发现精神分裂症患者大脑中的神经元染色质景观与早期胎儿发育有关。2025年10月27日，国际知名学术期刊《自然—神经科学》发表了这一成果。

课题组对1393个文库中2个新皮质区域的神经元和非神经元进行了大规模的染色质可及性分析。该团队观察到精神分裂症（SCZ）患者和对照组之间的神经元染色质可及性存在实质性差异，与SCZ风险位点相关的神经元中开放染色质区域（OCR）上调。SCZ相关的OCR与胎儿脑特异性OCR的比较显示，SCZ染色质的上调变化与胎儿皮质脑的开放性之间存在很强的相关性，将疾病相关的染色质改变与神经发育联系起来。

在这里，该课题组发现一个突出的神经元反调节结构域包含上调的OCR，巩固了关键的神经发育染色质特征，并在未成熟的谷氨酸能神经元中富集。这些发现将成人皮质染色质状态的改变与SCZ的早期发育机制联系起来。这项研究为人类皮层提供了一个全面的细胞类型分辨染色质可及性抵抗，并提供了对潜在SCZ风险的调控结构的见解。

据了解，非编码变异增加了神经精神疾病的风险，但对其细胞类型特异性作用的理解仍然不完整。

附：英文原文

Title: The neuronal chromatin landscape in brains from individuals with schizophrenia is linked to early fetal development

Author: Girdhar, Kiran, Bendl, Jaroslav, Baumgartner, Andrew, Therrien, Karen, Venkatesh, Sanan, Bercovitch, Rachel, Mathur, Deepika, Dong, Pengfei, Rahman, Samir, Kleopoulos, Steven P., Misir, Ruth, Reach, Sarah M., Auluck, Pavan K., Marenco, Stefano, Lewis, David A., Haroutunian, Vahram, Funk, Cory C., Voloudakis, Georgios, Hoffman, Gabriel E., Fullard, John F., Roussos, Panos

Issue&Volume: 2025-10-27

Abstract: Noncoding variants increase neuropsychiatric disease risk, but our understanding of their cell-type-specific role remains incomplete. We conducted large-scale chromatin accessibility profiling of neurons and non-neurons from 2 neocortical regions in 1,393 libraries. We observed substantial differences in neuronal chromatin accessibility between schizophrenia (SCZ) cases and controls, with upregulated open chromatin regions (OCRs) in neurons associated with SCZ risk loci. A comparison of SCZ-associated OCRs with fetal brain-specific OCRs revealed a strong correlation between upregulated changes in SCZ chromatin and openness in fetal cortical brains, linking disease-related chromatin alterations to neurodevelopment. Here we show that a prominent neuronal trans-regulatory domain containing upregulated OCRs consolidates key neurodevelopmental chromatin signatures and is enriched for immature glutamatergic neurons. These findings link altered adult cortical chromatin states to early developmental mechanisms in SCZ. This study provides a comprehensive cell-type-resolved chromatin accessibility resource for the human cortex and offers insights into the regulatory architecture underlying SCZ risk.

DOI: 10.1038/s41593-025-02081-3

Source: https://www.nature.com/articles/s41593-025-02081-3