Vrtn基因纯合敲除导致小鼠胚胎致死的多阶段转录组学分析

doi:10.16288/j.yczz.25-190

遗传 ›› 2026, Vol. 48 ›› Issue (3): 313-330.doi: 10.16288/j.yczz.25-190

Vrtn基因纯合敲除导致小鼠胚胎致死的多阶段转录组学分析

邓雅鑫¹(), 丁宝君¹, 李鸿春², 陈松¹, 张莹¹, 周波³(), 张震¹^,⁴()

1.桂林医科大学基础医学院，罕见病防治广西高校工程研究中心，桂林 541199
2.桂林医科大学公共卫生学院，桂林 541199
3.桂林医科大学科学实验中心，桂林 541199
4.中南大学湘雅基础医学院，长沙 410013

收稿日期:2025-07-04 修回日期:2025-10-27 出版日期:2026-03-20 发布日期:2025-11-21
通讯作者: 周波，博士，助理研究员，研究方向：生物医学。E-mail: zb090900021@163.com;
张震，博士，副教授，研究方向：遗传学。E-mail: zhenzhang@glmu.edu.cn
作者简介:邓雅鑫，硕士研究生，专业方向：生物医学。E-mail: 1528873272@qq.com
基金资助:
国家自然科学基金项目(32060139);广西自然科学基金项目(2025JJA130063);广西自然科学基金项目(2020GXNSFBA297026);桂林医科大学研究生创新项目(GYYK2025024);广西壮族自治区大学生创新创业训练项目(S202510601101)

Multi-stage transcriptomic analysis of mouse embryonic lethality induced by homozygous knockout of the Vrtn gene

Yaxin Deng¹(), Baojun Ding¹, Hongchun Li², Song Chen¹, Ying Zhang¹, Bo Zhou³(), Zhen Zhang¹^,⁴()

1. School of Basic Medical Sciences, Guangxi University Engineering Research Center for Rare Disease Prevention and Treatment, Guilin Medical University, Guilin 541199, China
2. School of Public Health, Guilin Medical University, Guilin 541199, China
3. Scientific Research Center, Guilin Medical University, Guilin 541199, China
4. Xiangya School of Basic Medical Sciences, Central South University, Changsha 410013, China

Received:2025-07-04 Revised:2025-10-27 Published:2026-03-20 Online:2025-11-21
Supported by:
National Natural Science Foundation of China(32060139);Natural Science Foundation of Guangxi Zhuang Autonomous Region(2025JJA130063);Natural Science Foundation of Guangxi Zhuang Autonomous Region(2020GXNSFBA297026);Graduate Research Program of Guilin Medical University(GYYK2025024);Guangxi Zhuang Autonomous Region Innovation and Entrepreneurship Training Program for College Students(S202510601101)

摘要/Abstract

摘要：

Vrtn基因是新近发现的与胚胎发育和干细胞多能性相关的基因，其纯合敲除(Vrtn^-/-)导致小鼠在胚胎期E12.5左右死亡。为阐明其致死机制，本研究整合形态学观察、多阶段转录组学分析及功能验证实验，揭示了由于Vrtn缺失引发的小鼠胚胎发育紊乱。形态学观察显示，Vrtn^-/-胚胎在E9.0、E9.5、E10.0、E10.5和E11.0发育期均呈现显著异常，表现为体轴缩短、神经管闭合缺陷、体节分化异常及心血管发育畸形，并伴随胚胎整体发育迟缓。通过转录组测序并结合qRT-PCR验证发现，Vrtn缺失一方面下调了与体节形成(Hoxa2、Hes5)、神经发育(Nefm、Nefl)及造血系统(Hbb-bh1、Klf1)相关基因表达；另一方面异常激活了细胞凋亡通路(Crabp2、Fam162a)和脂质代谢(Apom、Apoe)相关基因。TUNEL染色显示，Vrtn^-/-胚胎内细胞凋亡水平显著升高，同时Hif-1α免疫荧光检测表明缺氧应激反应被异常激活。甲状腺激素转运(Ttr)、DNA损伤应激(Ddit4)及脂质代谢(Apoa4、Apoa1)相关基因的广泛异常表达共同加剧了胚胎发育失衡，最终导致胚胎死亡。跨物种分析发现，在人类胚胎干细胞中敲降VRTN显著抑制血管生成核心基因(VEGFA、COL1A1和HES1)的表达，该结果与公共数据库中VRTN与缺氧响应的强关联性一致。综上所述，本研究阐明了Vrtn作为胚胎发育的调控基因，通过协调体节发生、神经分化、血管生成及缺氧应激响应等多个发育进程来维持胚胎稳态。这一发现不仅加深了对Vrtn基因在胚胎发育中作用机制的认识，也为解析相关遗传性疾病的发病机制提供了新视角。

关键词: Vrtn基因, 基因敲除, 转录组, 胚胎致死

Abstract:

The Vrtn gene, a recently identified regulator of embryonic development and stem cell pluripotency, is essential for embryonic survival, as its homozygous knockout (Vrtn^-/-) leads to lethality in mice at approximately embryonic day 12.5 (E12.5). To elucidate the underlying lethal mechanism, an integrated approach combining morphological observation, multi-stage transcriptomic analysis, and functional validation experiments was employed to systematically investigate the developmental disorders caused by Vrtn deficiency. Morphological observation showed that Vrtn^-/^- embryos exhibited significant abnormalities at developmental stages E9.0, E9.5, E10.0, E10.5, and E11.0, including shortened body axis, defective neural tube closure, aberrant somite differentiation, and cardiovascular malformations, accompanied by overall developmental delay. At the molecular level, through RNA sequencing and qRT-PCR validation revealed that Vrtn deficiency not only suppressed the expression of genes critical for somitogenesis (Hoxa2, Hes5), neurodevelopment (Nefm, Nefl), and the hematopoietic system (Hbb-bh1, Klf1), but also aberrantly activated genes associated with apoptosis (Crabp2, Fam162a) and lipid metabolism (Apom, Apoe). TUNEL staining showed that the level of apoptosis was significantly increased in Vrtn^-/- embryos. Meanwhile, immunofluorescence detection of Hif-1α indicated that the hypoxic stress response was aberrantly activated. Furthermore, the widespread dysregulation of genes involved in thyroid hormone transport (Ttr), DNA damage stress (Ddit4), and lipid metabolism (Apoa4, Apoa1) collectively exacerbated the developmental imbalance, ultimately leading to embryonic death. A cross-species analysis demonstrated that VRTN knockdown in human embryonic stem cells (hESCs) significantly suppressed the expression of core angiogenic genes (VEGFA, COL1A1 and HES1), a finding consistent with public database analyses indicating a strong association between VRTN and the hypoxic response. In conclusion, this study elucidates that Vrtn functions as a regulatory gene that maintains embryonic homeostasis by orchestrating multiple key developmental processes, including somitogenesis, neural differentiation, angiogenesis, and the hypoxic stress response. This discovery not only deepens the understanding of the role of Vrtn in embryonic development but also provides a new perspective for deciphering the pathogenesis of related hereditary diseases.

Key words: Vrtn gene, gene knockout, transcriptome, embryonic lethality

邓雅鑫, 丁宝君, 李鸿春, 陈松, 张莹, 周波, 张震. Vrtn基因纯合敲除导致小鼠胚胎致死的多阶段转录组学分析[J]. 遗传, 2026, 48(3): 313-330.

Yaxin Deng, Baojun Ding, Hongchun Li, Song Chen, Ying Zhang, Bo Zhou, Zhen Zhang. Multi-stage transcriptomic analysis of mouse embryonic lethality induced by homozygous knockout of the Vrtn gene[J]. Hereditas(Beijing), 2026, 48(3): 313-330.

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Vrtn基因纯合敲除导致小鼠胚胎致死的多阶段转录组学分析

Multi-stage transcriptomic analysis of mouse embryonic lethality induced by homozygous knockout of the Vrtn gene

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基因名称	引物序列(5′→3′)	扩增片段大小(bp)	退火温度(℃)
Hoxa2	F: TACGAATTTGAGCGAGAGATTGG	116	60
Hoxa2	R: GTCGAGGTCTTGATTGATGAACT
Hes5	F: AGTCCCAAGGAGAAAAACCGA	183	61
Hes5	R: GCTGTGTTTCAGGTAGCTGAC
Nefm	F: CTCGGCTATGCTCAGCTCG	96	59
Nefm	R: CGGGACAGTTTGTAGTCGCC
Nefl	F: CGCCGCTCTCAAGGACATC	129	60
Nefl	R: ACAGCGTCGGTGTTCTTGG
Hbb-bh1	F: GAAACCCCCGGATTAGAGCC	93	57
Hbb-bh1	R: GAGCAAAGGTCTCCTTGAGGT
Klf1	F: AGACTGTCTTACCCTCCATCAG	165	60
Klf1	R: GGTCCTCCGATTTCAGACTCAC
Vegfa	F: GCACATAGAGAGAATGAGCTTCC	105	61
Vegfa	R: CTCCGCTCTGAACAAGGCT
Bnip3	F: TCCTGGGTAGAACTGCACTTC	103	58
Bnip3	R: GCTGGGCATCCAACAGTATTT
Crabp2	F: ATGCCTAACTTTTCTGGCAACT	178	56
Crabp2	R: GCACAGTGGTGGAGGTTTTGA
Fam162a	F: AATGCTTCCTCGTCTCTAAGGT	117	61
Fam162a	R: CACCCCGTGTCTGTAAGACTG
Apom	F: TAACTCCATGAATCAGTGCCCT	105	60
Apom	R: CCCGCAATAAAGTACCACAGG
Apoe	F: CTGACAGGATGCCTAGCCG	107	57
Apoe	R: CGCAGGTAATCCCAGAAGC
Gapdh	F: AGGTCGGTGTGAACGGATTTG	123	60
Gapdh	R: TGTAGACCATGTAGTTGAGGTCA

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