自闭症与染色质三维结构关系的研究进展

doi:10.19586/j.2095-2341.2024.0206

生物技术进展 ›› 2025, Vol. 15 ›› Issue (3): 418-425.DOI: 10.19586/j.2095-2341.2024.0206

自闭症与染色质三维结构关系的研究进展

高海明(), 张媛媛, 何蓉()

中国医科大学附属盛京医院临床遗传科，沈阳 110004

收稿日期:2024-12-24 接受日期:2025-02-27 出版日期:2025-05-25 发布日期:2025-07-01
通讯作者: 何蓉
作者简介:高海明 E-mail: gaohm@sj-hospital.org；
基金资助:
辽宁省民生科技计划项目(2021JH2/10300121)

The Research Progress on the Relationship Between Autism and the Three-dimensional Structure of Chromosomes

Haiming GAO(), Yuanyuan ZHANG, Rong HE()

Department of Clinical Genetics，Shengjing Hospital，China Medical University，Shenyang 110004，China

Received:2024-12-24 Accepted:2025-02-27 Online:2025-05-25 Published:2025-07-01
Contact: Rong HE

摘要/Abstract

摘要：

自闭症谱系障碍（autism spectrum disorder，ASD）是一种发病率在1%~2%的复杂神经系统疾病，其发病具有显著的遗传异质性。三维基因组学研究揭示了染色质空间拓扑结构的动态调控在ASD病理机制中的核心作用，尤其是拓扑关联结构域（topologically associated domains，TADs）的边界破坏或内部互作紊乱，可通过表观遗传重编程导致神经发育关键基因的时空表达失调。然而，目前对ASD相关三维基因组变异尚未得到系统性解析以及现有临床诊断体系缺乏对三维基因组标志物的整合应用。系统综述了TADs介导的染色质区室化调控在ASD神经发展中的分子机制，总结了高通量染色体构象捕获技术（high-throughput chromosome conformation capture，Hi-C）及其衍生方法在ASD三维表观基因组图谱构建中的技术创新，以期为ASD的早期分子分型及靶向治疗提供理论支撑和技术范式。

关键词: 染色质三维结构, 自闭症谱系障碍, 拓扑关联结构域, 非编码区变异, Hi-C技术

Abstract:

Autism spectrum disorder （ASD） is a complex neurological disorder with an incidence rate of 1% to 2%， characterized by significant genetic heterogeneity. Three-dimensional genomics research has revealed the core role of dynamic regulation of chromatin spatial topology in the pathological mechanism of ASD， especially the disruption of boundaries or internal interactions within topologically associated domains （TADs）， which could lead to spatiotemporal expression dysregulation of key neurodevelopmental genes through epigenetic reprogramming. However，ASD-related three-dimensional genomic variations related has not been systematically clarified and the existing clinical diagnostic system lacks the integrated application of three-dimensional genomic markers. The article systematically reviewed the molecular mechanisms of TAD-mediated chromatin compartmentalization regulation in ASD neurodevelopment and summarized the technological innovations of high-throughput chromosome conformation capture technology （Hi-C） and its derivative methods in the construction of three-dimensional epigenomic maps of ASD， in order to provide theoretical support and technical paradigms for the early molecular typing and targeted treatment of ASD.

Key words: chromosome three-dimensional structure, autism spectrum disorder, topologically associated domains, non-coding region variation, Hi-C technology

中图分类号:

高海明, 张媛媛, 何蓉. 自闭症与染色质三维结构关系的研究进展[J]. 生物技术进展, 2025, 15(3): 418-425.

Haiming GAO, Yuanyuan ZHANG, Rong HE. The Research Progress on the Relationship Between Autism and the Three-dimensional Structure of Chromosomes[J]. Current Biotechnology, 2025, 15(3): 418-425.

图/表 4

参考文献 52

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分类	子类	关键机制	参考文献
遗传因素	DNVs	神经发育相关基因功能破坏	[2-3]
	罕见SNVs/CNVs	单核苷酸/小片段变异（52%）、染色体结构变异（46%）直接破坏关键基因或调控元件	[3]
	多基因风险评分	常见SNPs叠加效应	[7-9]
	父母生育年龄	父系年龄增长导致生殖细胞DNVs增加	[2]
	性别差异	女性需更高遗传负荷；X染色体失活和性激素可能增强耐受性	[9]
表观遗传因素	非编码区结构变异	破坏启动子/增强子与远端基因的染色质三维互作，干扰时空特异性表达	[4-7,9-15]
环境因素	孕期暴露	炎症、氧化应激等	[9]

分类	子类	关键机制	参考文献
遗传因素	DNVs	神经发育相关基因功能破坏	[2-3]
	罕见SNVs/CNVs	单核苷酸/小片段变异（52%）、染色体结构变异（46%）直接破坏关键基因或调控元件	[3]
	多基因风险评分	常见SNPs叠加效应	[7-9]
	父母生育年龄	父系年龄增长导致生殖细胞DNVs增加	[2]
	性别差异	女性需更高遗传负荷；X染色体失活和性激素可能增强耐受性	[9]
表观遗传因素	非编码区结构变异	破坏启动子/增强子与远端基因的染色质三维互作，干扰时空特异性表达	[4-7,9-15]
环境因素	孕期暴露	炎症、氧化应激等	[9]

机制类型	具体机制	病理影响	参考文献
TAD边界功能异常	TAD边界表观遗传标记异常或结构破坏，导致增强子-启动子异位互作	神经发育关键基因异常表达，影响神经前体细胞增殖与分化	[31-32]
CTCF蛋白功能失调	CTCF绝缘边界功能丧失或染色质可及性维持异常，破坏三维基因组稳定性	基因异位激活或抑制，多能性基因表达失衡，影响神经分化	[33]
三维互作网络紊乱	增强子-启动子长距离或跨染色体互作模式改变，破坏时空特异性转录调控	神经发育关键期转录程序失调，引发突触功能及剪接异常	[4,8]
基因组结构变异	TADs融合（增强子劫持）或边界缺失（增强子释放-重定向）导致的调控网络重构	神经发育相关基因（如皮层形态发生基因）表达异常	[34-36]
相分离调控失衡	转录因子介导的相分离异常，导致染色质动态重组与细胞类型特异性染色质环形成障碍	神经细胞命运决定异常，重编程过程受阻	[37]
拓扑结构早发性改变	亚核区室化重构、TAD连接强度异常等三维结构变化早于转录异常	可作为ASD早期诊断标志，提示神经发育调控网络初始紊乱	[38]

机制类型	具体机制	病理影响	参考文献
TAD边界功能异常	TAD边界表观遗传标记异常或结构破坏，导致增强子-启动子异位互作	神经发育关键基因异常表达，影响神经前体细胞增殖与分化	[31-32]
CTCF蛋白功能失调	CTCF绝缘边界功能丧失或染色质可及性维持异常，破坏三维基因组稳定性	基因异位激活或抑制，多能性基因表达失衡，影响神经分化	[33]
三维互作网络紊乱	增强子-启动子长距离或跨染色体互作模式改变，破坏时空特异性转录调控	神经发育关键期转录程序失调，引发突触功能及剪接异常	[4,8]
基因组结构变异	TADs融合（增强子劫持）或边界缺失（增强子释放-重定向）导致的调控网络重构	神经发育相关基因（如皮层形态发生基因）表达异常	[34-36]
相分离调控失衡	转录因子介导的相分离异常，导致染色质动态重组与细胞类型特异性染色质环形成障碍	神经细胞命运决定异常，重编程过程受阻	[37]
拓扑结构早发性改变	亚核区室化重构、TAD连接强度异常等三维结构变化早于转录异常	可作为ASD早期诊断标志，提示神经发育调控网络初始紊乱	[38]

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自闭症与染色质三维结构关系的研究进展

The Research Progress on the Relationship Between Autism and the Three-dimensional Structure of Chromosomes

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