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

doi:10.19586/j.2095-2341.2024.0206

Current Biotechnology ›› 2025, Vol. 15 ›› Issue (3): 418-425.DOI: 10.19586/j.2095-2341.2024.0206

• Reviews • Previous Articles Next Articles

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

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

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)

Abstract

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

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

CLC Number:

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.

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.

Figures/Tables 4

References 52

1	GESCHWIND D H, FLINT J. Genetics and genomics of psychiatric disease[J]. Science, 2015, 349(6255): 1489-1494.
2	ANTAKI D, GUEVARA J, MAIHOFER A X, et al.. A phenotypic spectrum of autism is attributable to the combined effects of rare variants, polygenic risk and sex[J]. Nat. Genet., 2022, 54(9): 1284-1292.
3	NAKAMURA T, UEDA J, MIZUNO S, et al.. Topologically associating domains define the impact of de novo promoter variants on autism spectrum disorder risk[J/OL]. Cell Genom., 2024, 4(2): 100488[2025-04-09]. .
4	CARBALLO-PACORET P, CARRACEDO A, RODRIGUEZ-FONTENLA C. Unraveling the three-dimensional (3D) genome architecture in neurodevelopmental disorders (NDDs)[J]. Neurogenetics, 2024, 25(4): 293-305.
5	MALACHOWSKI T, CHANDRADOSS K R, BOYA R, et al.. Spatially coordinated heterochromatinization of long synaptic genes in fragile X syndrome[J]. Cell, 2023, 186(26): 5840-5858.
6	SANDIN S, LICHTENSTEIN P, KUJA-HALKOLA R, et al.. The heritability of autism spectrum disorder[J]. JAMA, 2017, 318(12): 1182-1184.
7	KAAIJ L J T, MOHN F, VAN DER WEIDE R H, et al.. The ChAHP complex counteracts chromatin looping at CTCF sites that emerged from SINE expansions in mouse[J]. Cell, 2019, 178(6): 1437-1451.
8	KIM I B, LEE T, LEE J, et al.. Non-coding de novo mutations in chromatin interactions are implicated in autism spectrum disorder[J]. Mol. Psychiatr., 2022, 27(11): 4680-4694.
9	HONYBUN E, COCKLE E, MALPAS C B, et al.. Neurodevelopmental and functional outcomes following in utero exposure to antiseizure medication: a systematic review[J/OL]. Neurology, 2024, 102(8): e209175[2025-04-09]. .
10	RUZZO E K, PÉREZ-CANO L, JUNG J Y, et al.. Inherited and de novo genetic risk for autism impacts shared networks[J]. Cell, 2019, 178(4): 850-866.
11	COHEN S, GABEL H W, HEMBERG M, et al.. Genome-wide activity-dependent MeCP2 phosphorylation regulates nervous system development and function[J]. Neuron, 2011, 72(1): 72-85.
12	BERNIER R, GOLZIO C, XIONG B, et al.. Disruptive CHD8 mutations define a subtype of autism early in development[J]. Cell, 2014, 158(2): 263-276.
13	CIRNIGLIARO M, CHANG T S, ARTEAGA S A, et al.. The contributions of rare inherited and polygenic risk to ASD in multiplex families[J/OL]. Proc. Natl. Acad. Sci. USA, 2023, 120(31): e2215632120[2025-04-09]. .
14	GROTZINGER A D, MALLARD T T, AKINGBUWA W A, et al.. Genetic architecture of 11 major psychiatric disorders at biobehavioral, functional genomic and molecular genetic levels of analysis[J]. Nat. Genet., 2022, 54(5): 548-559.
15	AN J Y, LIN K, ZHU L, et al.. Genome-wide de novo risk score implicates promoter variation in autism spectrum disorder[J/OL]. Science, 2018, 362(6420): eaat6576[2025-04-09]. .
16	TROST B, THIRUVAHINDRAPURAM B, CHAN A J S, et al.. Genomic architecture of autism from comprehensive whole-genome sequence annotation[J]. Cell, 2022, 185(23): 4409-4427.
17	FELICIANO P, ZHOU X, WANG T, et al.. eP121: integrating de novo and inherited variants in over 42607 autism cases identifies variants in new moderate risk genes[J/OL]. Genet. Med., 2022, 24(3): S76[2025-04-09]. .
18	TURNER T N, COE B P, DICKEL D E, et al.. Genomic patterns of de novo mutation in simplex autism[J]. Cell, 2017, 171(3): 710-722.
19	DU Z, ZHENG H, HUANG B, et al.. Allelic reprogramming of 3D chromatin architecture during early mammalian development[J]. Nature, 2017, 547(7662): 232-235.
20	ZHONG H, ZHANG J, LU Y, et al.. 3D genome perspective on cell fate determination, regenerationorgan, and diseases[J/OL]. Cell Prolif., 2023, 56(5): e13482[2025-04-09]. .
21	FUDENBERG G, IMAKAEV M, LU C, et al.. Formation of chromosomal domains by loop extrusion[J]. Cell Rep., 2016, 15(9): 2038-2049.
22	TOROSIN N S, ANAND A, GOLLA T R, et al.. 3D genome evolution and reorganization in the Drosophila melanogaster species group[J/OL]. PLoS Genet., 2020, 16(12): e1009229[2025-04-09]. .
23	ZAGIROVA D, KONONKOVA A, VAULIN N, et al.. From compartments to loops: understanding the unique chromatin organization in neuronal cells[J/OL]. Epigenet. Chromatin, 2024, 17(1): 18[2025-04-09]. .
24	PHILLIPS-CREMINS J E, SAURIA M E G, SANYAL A, et al.. Architectural protein subclasses shape 3D organization of genomes during lineage commitment[J]. Cell, 2013, 153(6): 1281-1295.
25	ZUIN J, DIXON J R, VAN DER REIJDEN M I J A, et al.. Cohesin and CTCF differentially affect chromatin architecture and gene expression in human cells[J]. Proc. Natl. Acad. Sci. USA, 2014, 111(3): 996-1001.
26	SZABO Q, BANTIGNIES F, CAVALLI G. Principles of genome folding into topologically associating domains[J/OL]. Sci. Adv., 2019, 5(4): eaaw1668[2025-04-09]. .
27	KREFTING J, ANDRADE-NAVARRO M A, IBN-SALEM J. Evolutionary stability of topologically associating domains is associated with conserved gene regulation[J/OL]. BMC Biol., 2018, 16(1): 87[2025-04-09]. .
28	MCARTHUR E, CAPRA J A. Topologically associating domain boundaries that are stable across diverse cell types are evolutionarily constrained and enriched for heritability[J]. Am. J. Hum. Genet., 2021, 108(2): 269-283.
29	ZHANG D, HUANG P, SHARMA M, et al.. Alteration of genome folding via contact domain boundary insertion[J]. Nat. Genet., 2020, 52(10): 1076-1087.
30	NARENDRA V, ROCHA P P, AN D, et al.. CTCF establishes discrete functional chromatin domains at the Hox clusters during differentiation[J]. Science, 2015, 347(6225): 1017-1021.
31	DE RUBEIS S, HE X, GOLDBERG A P, et al.. Synaptic, transcriptional and chromatin genes disrupted in autism[J]. Nature, 2014, 515(7526): 209-215.
32	LU H, YU D, HANSEN A S, et al.. Phase-separation mechanism for C-terminal hyperphosphorylation of RNA polymerase Ⅱ‍[J]. Nature, 2018, 558(7709): 318-323.
33	SONG Y, LIANG Z, ZHANG J, et al.. CTCF functions as an insulator for somatic genes and a chromatin remodeler for pluripotency genes during reprogramming[J/OL]. Cell Rep., 2022, 39(1): 110626[2025-04-09]. .
34	ANDREY G, MUNDLOS S. The three-dimensional genome: regulating gene expression during pluripotency and development[J]. Development, 2017, 144(20): 3646-3658.
35	OH S, SHAO J, MITRA J, et al.. Enhancer release and retargeting activates disease-susceptibility genes[J]. Nature, 2021, 595(7869): 735-740.
36	MAKOWSKI C, VAN DER MEER D, DONG W, et al.. Discovery of genomic loci of the human cerebral cortex using genetically informed brain atlases[J]. Science, 2022, 375(6580): 522-528.
37	WANG J, YU H, MA Q, et al.. Phase separation of OCT4 controls TAD reorganization to promote cell fate transitions[J]. Cell Stem Cell, 2021, 28(10): 1868-1883.
38	KRIJGER P H L, DI STEFANO B, DE WIT E, et al.. Cell-of-origin-specific 3D genome structure acquired during somatic cell reprogramming[J]. Cell Stem Cell, 2016, 18(5): 597-610.
39	BEAGAN J A, PASTUZYN E D, FERNANDEZ L R, et al.. Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression[J]. Nat. Neurosci., 2020, 23(6): 707-717.
40	WILFERT A B, TURNER T N, MURALI S C, et al.. Recent ultra-rare inherited variants implicate new autism candidate risk genes[J]. Nat. Genet., 2021, 53(8): 1125-1134.
41	ANANIA C, ACEMEL R D, JEDAMZICK J, et al.. In vivo dissection of a clustered-CTCF domain boundary reveals developmental principles of regulatory insulation[J]. Nat. Genet., 2022, 54(7): 1026-1036.
42	HUYNH L, HORMOZDIARI F. TAD fusion score: discovery and ranking the contribution of deletions to genome structure[J/OL]. Genome Biol., 2019, 20(1): 60[2025-04-09]. .
43	JERKOVIC I, CAVALLI G. Understanding 3D genome organization by multidisciplinary methods[J]. Nat. Rev. Mol. Cell Biol., 2021, 22(8): 511-528.
44	MOHANTA T K, MISHRA A K, AL-HARRASI A. The 3D genome: from structure to function[J/OL]. Int. J. Mol. Sci., 2021, 22(21): 11585[2025-04-09]. .
45	LIEBERMAN-AIDEN E, VAN BERKUM N L, WILLIAMS L, et al.. Comprehensive mapping of long-range interactions reveals folding principles of the human genome[J]. Science, 2009, 326(5950): 289-293.
46	MOTA-GÓMEZ I, LUPIÁÑEZ D G. A (3D-nuclear) space odyssey: making sense of Hi-C maps[J/OL]. Genes, 2019, 10(6): 415[2025-04-09]. .
47	RAO S S P, HUNTLEY M H, DURAND N C, et al.. A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping[J]. Cell, 2014, 159(7): 1665-1680.
48	SIKORSKA N, SEXTON T. Defining functionally relevant spatial chromatin domains: it is a TAD complicated[J]. J. Mol. Biol., 2020, 432(3): 653-664.
49	ZHANG S, HE Y, LIU H, et al.. regBase: whole genome base-wise aggregation and functional prediction for human non-coding regulatory variants[J/OL]. Nucleic Acids Res., 2019, 47(21): e134[2025-04-09]. .
50	WANG Z, ZHAO G, LI B, et al.. Performance comparison of computational methods for the prediction of the function and pathogenicity of non-coding variants[J]. Genom. Proteom. Bioinform., 2023, 21(3): 649-661.
51	HE Z, LIU L, BELLOY M E, et al.. Ghost knockoff inference empowers identification of putative causal variants in genome-wide association studies[J/OL]. Nat. Commun., 2022, 13(1): 7209[2025-04-09]. .
52	HE Z, LIU L, WANG C, et al.. Identification of putative causal loci in whole-genome sequencing data via knockoff statistics[J/OL]. Nat. Commun., 2021, 12(1): 3152[2025-04-09]. .

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]

[1]	Jingjing FANG, Kunlun HUANG, Tao TONG. Research Progress on Experimental Models of Autism Spectrum Disorders [J]. Current Biotechnology, 2023, 13(4): 509-523.
[2]	YUAN Qifeng, YAO Baozhen^*. Progress of Abnormal Glutamate-glutamine Cycle in Autism Spectrum Disorders [J]. Curr. Biotech., 2021, 11(2): 170-175.

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

自闭症与染色质三维结构关系的研究进展

RichHTML

PDF

Knowledge

Abstract

Cite this article

share this article

Figures/Tables 4

References 52

Related Articles 2

Recommended Articles

Metrics

Comments