美国宾夕法尼亚大学Jennifer E. Phillips-Cremins和犹他大学Jason D. Shepherd研究团队合作，揭示了活动诱导的神经元基因表达跨时间尺度的三维基因组重构。该研究成果于2020年5月25日发表在《自然—神经科学》上。

研究人员使用高分辨率染色体构象捕获碳复制测序（5C-seq）技术来阐明，短期和长期的神经活动变化过程中，长距离染色质环的改变程度。研究发现在皮层神经元激活过程中从头诱导了围绕立早基因（IEGs）、次级反应基因（SRGs）和突触基因选择环的10％以上。IEG Fos和Arc通过单一的短程环与活动相关的增强子相连，该短程环在受到刺激后20分钟内且在信使RNA达到峰值之前形成。

相比之下，SRG Bdnf参与了1–6 h内所形成的既有环路和活动诱导环路。研究人员还发现，与自闭症和精神分裂症相关的常见单核苷酸变体与活动依赖的环状增强子之间存在不同类别的共定位。该研究数据将体系结构的复杂性与转录动力学联系起来，并揭示了在神经元刺激过程中高阶染色质体系重构所需要的时间尺度。

附：英文原文

Title: Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression

Author: Jonathan A. Beagan, Elissa D. Pastuzyn, Lindsey R. Fernandez, Michael H. Guo, Kelly Feng, Katelyn R. Titus, Harshini Chandrashekar, Jason D. Shepherd, Jennifer E. Phillips-Cremins

Issue&Volume: 2020-05-25

Abstract: Neuronal activation induces rapid transcription of immediate early genes (IEGs) and longer-term chromatin remodeling around secondary response genes (SRGs). Here, we use high-resolution chromosome-conformation-capture carbon-copy sequencing (5C-seq) to elucidate the extent to which long-range chromatin loops are altered during short- and long-term changes in neural activity. We find that more than 10% of loops surrounding select IEGs, SRGs, and synaptic genes are induced de novo during cortical neuron activation. IEGs Fos and Arc connect to activity-dependent enhancers via singular short-range loops that form within 20min after stimulation, prior to peak messenger RNA levels. By contrast, the SRG Bdnf engages in both pre-existing and activity-inducible loops that form within 1–6h. We also show that common single-nucleotide variants that are associated with autism and schizophrenia are colocalized with distinct classes of activity-dependent, looped enhancers. Our data link architectural complexity to transcriptional kinetics and reveal the rapid timescale by which higher-order chromatin architecture reconfigures during neuronal stimulation.

DOI: 10.1038/s41593-020-0634-6

Source: https://www.nature.com/articles/s41593-020-0634-6