Neuron-specific signatures in the chromosomal connectome associated with schizophrenia risk
Neuron-specific signatures in the chromosomal connectome associated with schizophrenia risk
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DOI：
10.1126/science.aat4311
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发表时间：
2018-12-14
期刊：
影响因子：
56.9
通讯作者：
Akbarian, Schahram
中科院分区：
文献类型：
--
作者：
Rajarajan, Prashanth;Borrman, Tyler;Akbarian, Schahram
为了探索神经精神疾病背景下大脑三维基因组的发育重组，我们监测了神经前体细胞分化过程中的染色体构象。神经元和神经胶质细胞的分化与广泛的染色体接触图的发育重塑有关，并包括锚定在共同变异序列中的相互作用，这些变异序列赋予了精神分裂症的遗传风险。我们描述了由精神分裂症风险变体及其远端靶点组成的特定细胞类型的染色体连接，这些连接总共显示了调控神经元连接和染色质重塑的基因的丰富，以及参与基因的协调转录调控和蛋白质组相互作用的证据。发育调节的精神分裂症相关序列的染色体构象变化在神经元中不成比例地发生，突显了空间基因组组织中存在细胞类型特定的疾病风险脆弱性。
To explore the developmental reorganization of the three-dimensional genome of the brain in the context of neuropsychiatric disease, we monitored chromosomal conformations in differentiating neural progenitor cells. Neuronal and glial differentiation was associated with widespread developmental remodeling of the chromosomal contact map and included interactions anchored in common variant sequences that confer heritable risk for schizophrenia. We describe cell type-specific chromosomal connectomes composed of schizophrenia risk variants and their distal targets, which altogether show enrichment for genes that regulate neuronal connectivity and chromatin remodeling, and evidence for coordinated transcriptional regulation and proteomic interaction of the participating genes. Developmentally regulated chromosomal conformation changes at schizophrenia-relevant sequences disproportionally occurred in neurons, highlighting the existence of cell type-specific disease risk vulnerabilities in spatial genome organization.