UNC Neuroscience Center, University of North Carolina, Chapel Hill, NC, USA.
Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
Nat Commun. 2021 Jun 25;12(1):3968. doi: 10.1038/s41467-021-24243-0.
Cellular heterogeneity in the human brain obscures the identification of robust cellular regulatory networks, which is necessary to understand the function of non-coding elements and the impact of non-coding genetic variation. Here we integrate genome-wide chromosome conformation data from purified neurons and glia with transcriptomic and enhancer profiles, to characterize the gene regulatory landscape of two major cell classes in the human brain. We then leverage cell-type-specific regulatory landscapes to gain insight into the cellular etiology of several brain disorders. We find that Alzheimer's disease (AD)-associated epigenetic dysregulation is linked to neurons and oligodendrocytes, whereas genetic risk factors for AD highlighted microglia, suggesting that different cell types may contribute to disease risk, via different mechanisms. Moreover, integration of glutamatergic and GABAergic regulatory maps with genetic risk factors for schizophrenia (SCZ) and bipolar disorder (BD) identifies shared (parvalbumin-expressing interneurons) and distinct cellular etiologies (upper layer neurons for BD, and deeper layer projection neurons for SCZ). Collectively, these findings shed new light on cell-type-specific gene regulatory networks in brain disorders.
人脑中的细胞异质性掩盖了稳健的细胞调控网络的识别，而这对于理解非编码元件的功能和非编码遗传变异的影响是必要的。在这里，我们整合了来自纯化神经元和神经胶质细胞的全基因组染色体构象数据，以及转录组和增强子谱，以描绘人类大脑中两个主要细胞类型的基因调控景观。然后，我们利用细胞类型特异性调控景观来深入了解几种脑部疾病的细胞病因。我们发现，阿尔茨海默病（AD）相关的表观遗传失调与神经元和少突胶质细胞有关，而 AD 的遗传风险因素则突出了小胶质细胞，这表明不同的细胞类型可能通过不同的机制对疾病风险做出贡献。此外，将谷氨酸能和 GABA 能调控图谱与精神分裂症（SCZ）和双相情感障碍（BD）的遗传风险因素进行整合，确定了共享的（表达 parvalbumin 的中间神经元）和独特的细胞病因（BD 为上层神经元，SCZ 为深层投射神经元）。总的来说，这些发现为脑部疾病中的细胞类型特异性基因调控网络提供了新的视角。
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