新型冠状病毒（SARS-COV-2）感染后人嗅觉神经上皮细胞的基因组调控网络研究

doi:10.3969/j.issn.1674-8115.2022.11.002

上海交通大学学报（医学版） ›› 2022, Vol. 42 ›› Issue (11): 1524-1533.doi: 10.3969/j.issn.1674-8115.2022.11.002

• 论著 · 基础研究 • 上一篇

新型冠状病毒（SARS-COV-2）感染后人嗅觉神经上皮细胞的基因组调控网络研究

解昕轶¹(), 杨钰萌¹, 王少薇¹, 孙娜², 史传道², 刘启玲², 张荣强²(), 李俊杰¹

^1.陕西中医药大学第二临床医学院临床医学系，咸阳 712046
^2.陕西中医药大学公共卫生学院流行病与卫生统计学教研室，咸阳 712046

收稿日期:2022-04-29 接受日期:2022-10-18 出版日期:2022-11-28 发布日期:2023-01-04
通讯作者: 张荣强 E-mail:3025680438@qq.com;zhangrq2003@sntcm.edu.cn
作者简介:解昕轶（1999—），女，本科生；电子信箱：3025680438@qq.com。
基金资助:
2022年中央财政重大传染病防控专项经费;大学生创新训练计划项目(S202010716009);陕西中医药大学慢性非传染性疾病病因及机制研究创新团队(132041933)

Genomic regulatory network of human olfactory neuroepithelial cells infected with novel coronavirus (SARS-COV-2)

XIE Xinyi¹(), YANG Yumeng¹, WANG Shaowei¹, SUN Na², SHI Chuandao², LIU Qiling², ZHANG Rongqiang²(), LI Junjie¹

^1.Department of Clinical Medicine, The Second Clinical School, Shaanxi University of Chinese Medicine, Xianyang 712046, China
^2.Department of Epidemiology and Health Statistics, School of Public Health, Shaanxi University of Chinese Medicine, Xianyang 712046, China

Received:2022-04-29 Accepted:2022-10-18 Online:2022-11-28 Published:2023-01-04
Contact: ZHANG Rongqiang E-mail:3025680438@qq.com;zhangrq2003@sntcm.edu.cn
Supported by:
Special Funds of the Central Government for the Prevention and Control of Major Infectious Diseases;College Students′ Innovation Training Program(S202010716009);Shaanxi University of Chinese Medicine Research Innovation Team on Etiology and Mechanism of Chronic Non-Infectious Diseases(132041933)

摘要/Abstract

摘要：

目的·探索新型冠状病毒（SARS-COV-2）感染人体后，人嗅觉神经上皮细胞的基因组学变化，建立差异表达基因（differentially expressed genes，DEGs）的蛋白互作（protein-protein interactions，PPI）网络等，了解SARS-COV-2感染对人嗅觉神经上皮细胞的影响，为新型冠状病毒肺炎的防治提供参考依据。方法·采用NetworkAnalyst分析公共数据集GSE151973，挑选DEGs，进行基因本体（Gene Ontology，GO）和京都基因与基因组百科全书（Kyoto Encyclopedia of Genes and Genomes，KEGG）信号通路分析，创建PPI网络、DEGs-microRNA调控网络、转录因子-DEGs调控网络、环境化学物-DEGs调控网络以及药物-DEGs调控网络，使用Cytoscape 3.7.2进行图视化。结果·SAR-COV-2侵袭人嗅觉神经上皮细胞后，基因表达谱部分发生明显上调或下调，共发现了568个DEGs，其中上调基因550个（96.8%），下调基因18个（3.2%）；通过富集分析，DEGs主要参与鼻呼吸和嗅觉上皮的内皮发育、血管生成等生物学过程，N端肉豆蔻酰化结构域结合等分子功能表达。PPI网络提示RTP1和RTP2为核心蛋白；MAZ为最具有影响效应的转录因子；Hsa-mir-26b-5p对DEGs的调控作用最明显；环境化学物丙戊酸钠对DEG最具影响；药物乙醇对DEGs的调控最具有影响。结论·感染SAR-COV-2后嗅觉神经上皮细胞基因表达明显改变，SARS-CoV-2可能通过抑制PAX7功能来抑制肌肉卫星细胞的增殖分化。RTP1、RTP2可能通过促嗅觉受体上膜的能力以及其对气味配体反应性抵抗SARS-CoV-2，MAZ可能通过影响细胞的生长、增殖调控DEGs；microRNA、环境化学物和药物在人嗅觉神经上皮细胞抗SAR-COV-2感染过程中也发挥着不可忽视的作用。

关键词: COVID-19, 新型冠状病毒（SARS-CoV-2）, 嗅觉神经上皮细胞

Abstract:

Objective To explore the genomic changes of human olfactory neuroepithelial cells after the novel coronavirus (SARS-COV-2) infecting the human body, and establish a protein-protein interaction (PPI) network of differentially expressed genes (DEGs), in order to understand the impact of SARS-COV-2 infection on human olfactory neuroepithelial cells, and provide reference for the prevention and treatment of new coronavirus pneumonia. Methods The public dataset GSE151973 was analyzed by NetworkAnalyst. DEGs were selected by conducting Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) signal pathway analysis. PPI network, DEGs-microRNA regulatory network, transcription factor-DEGs regulatory network, environmental chemicals-DEGs regulatory network, and drug-DEGs regulatory network were created and visualized by using Cytoscape 3.7.2. Results After SAR-COV-2 invading human olfactory neuroepithelial cells, part of the gene expression profile was significantly up-regulated or down-regulated. A total of 568 DEGs were found, including 550 up-regulated genes (96.8%) and 18 down-regulated genes (3.2%). DEGs were mainly involved in biological processes such as endothelial development and angiogenesis of the olfactory epithelium, and the expression of molecular functions such as the binding of the N-terminal myristylation domain. PPI network suggested that RTP1 and RTP2 were core proteins. MAZ was the most influential transcription factor. Hsa-mir-26b-5p had the most obvious interaction with DEGs regulation. Environmental chemical valproic acid and drug ethanol had the most influence on the regulation of DEG. Conclusion The gene expression of olfactory neuroepithelial cells is significantly up-regulated or down-regulated after infection with SAR-COV-2. SARS-CoV-2 may inhibit the proliferation and differentiation of muscle satellite cells by inhibiting the function of PAX7. RTP1 and RTP2 may resist SARS-CoV-2 by promoting the ability of olfactory receptors to coat the membrane and enhancing the ability of olfactory receptors to respond to odorant ligands. MAZ may regulate DEGs by affecting cell growth and proliferation. Micro RNA, environmental chemicals and drugs also play an important role in the anti-SAR-COV-2 infection process of human olfactory neuroepithelial cells.

Key words: COVID-19, SARS-CoV-2, olfactory neuroepithelial cells

中图分类号:

R183.3

解昕轶, 杨钰萌, 王少薇, 孙娜, 史传道, 刘启玲, 张荣强, 李俊杰. 新型冠状病毒（SARS-COV-2）感染后人嗅觉神经上皮细胞的基因组调控网络研究[J]. 上海交通大学学报（医学版）, 2022, 42(11): 1524-1533.

XIE Xinyi, YANG Yumeng, WANG Shaowei, SUN Na, SHI Chuandao, LIU Qiling, ZHANG Rongqiang, LI Junjie. Genomic regulatory network of human olfactory neuroepithelial cells infected with novel coronavirus (SARS-COV-2)[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2022, 42(11): 1524-1533.

图/表 8

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Down-regulated DEGs	Full name	Log2 FoldChange	FDR	Up-regulated DEGs（Top 20）	Full name	Log2 FoldChange	FDR
PAX7	Paired box 7	-4.12	6.80×10^-6	ACNATP	Acyl-CoA： amino acid N-acyltransferase pseudogene	12.87	3.05×10^-15
LINC00491	Long intergenic non-protein coding RNA 491	-3.05	1.79×10^-3	CNGA2	Cyclic nucleotide gated channel subunit alpha 2	11.62	2.95×10^-12
BMP3	Bone morphogenetic protein 3	-3.02	1.03×10^-3	OR4K2	Olfactory receptor family 4 subfamily K member 2	11.48	2.26×10^-11
CEACAM5	CEA cell adhesion molecule 5	-2.77	7.56×10^-3	ARHGDIG	Rho GDP dissociation inhibitor gamma	11.41	1.98×10^-12
B3GALT5	Beta-1， 3-galactosyltransferase 5	-2.44	2.47×10^-3	CELF3	CUGBP Elav-like family member 3	10.65	5.07×10^-10
SERPINB10	Serpin family B member 10	-2.42	3.81×10^-3	SLC17A6	Solute carrier family 17 member 6	10.23	3.61×10^-10
SERPINB4	Serpin family B member 4	-2.37	1.01×10^-2	OR2I1P	Olfactory receptor family 2 subfamily I member 1 pseudogene	10.20	1.03×10^-7
CYP2F2P	Cytochrome P450 family 2 subfamily F member 2， pseudogene	-2.33	5.01×10^-3	DPP6	Dipeptidyl peptidase like 6	10.11	1.68×10^-8
CYP2F1	Cytochrome P450 family 2 subfamily F member 1	-2.31	2.33×10^-5	CYP1A2	Cytochrome P450 family 1 subfamily A member 2	9.94	2.83×10^-9
ATP12A	ATPase H⁺/K⁺ transporting non-gastric alpha2 subunit	-2.30	1.70×10^-3	OR4D9	Olfactory receptor family 4 subfamily D member 9	9.92	2.16×10^-6
HORMAD1	HORMA domain containing 1	-2.26	3.05×10^-2	OR2T10	Olfactory receptor family 2 subfamily T member 10	9.89	2.41×10^-8
EDAR	Ectodysplasin A receptor	-2.23	2.02×10^-2	CPLX2	Complexin 2	9.82	4.16×10^-9
PTPRH	Protein tyrosine phosphatase receptor type H	-2.23	1.89×10^-2	OR2V2	Olfactory receptor family 2 subfamily V member 2	9.81	1.32×10^-9
AL512274.1	Homo sapiens chromosome 6 clone RP11-7K24	-2.14	2.18×10^-2	GFY	Golgi associated olfactory signaling regulator	9.78	4.25×10^-7
FOXQ1	Forkhead box Q1	-2.09	9.28×10^-3	OR2B11	Olfactory receptor family 2 subfamily B member 11	9.75	6.00×10^-5
AC044893.1	Homo sapiens chromosome 8 clone RP11-696E24 map 8， LOW-PASS SEQUENCE SAMPLING	-2.06	6.04×10^-3	FSTL5	Follistatin like 5	9.59	3.49×10^-53
KLK11	Kallikrein related peptidase 11	-2.02	2.80×10^-2	OR4E1	Olfactory receptor family 4 subfamily E member 1	9.56	6.86×10^-7
TMPRSS4	Transmembrane serine protease 4	-2.01	1.40×10^-2	OR4K17	Olfactory receptor family 4 subfamily K member 17	9.55	2.12×10^-7
				ZAN	Zonadhesin	9.52	1.25×10^-7
				SLC24A2	Solute carrier family 24 member 2	9.47	5.07×10^-10

Down-regulated DEGs	Full name	Log2 FoldChange	FDR	Up-regulated DEGs（Top 20）	Full name	Log2 FoldChange	FDR
PAX7	Paired box 7	-4.12	6.80×10^-6	ACNATP	Acyl-CoA： amino acid N-acyltransferase pseudogene	12.87	3.05×10^-15
LINC00491	Long intergenic non-protein coding RNA 491	-3.05	1.79×10^-3	CNGA2	Cyclic nucleotide gated channel subunit alpha 2	11.62	2.95×10^-12
BMP3	Bone morphogenetic protein 3	-3.02	1.03×10^-3	OR4K2	Olfactory receptor family 4 subfamily K member 2	11.48	2.26×10^-11
CEACAM5	CEA cell adhesion molecule 5	-2.77	7.56×10^-3	ARHGDIG	Rho GDP dissociation inhibitor gamma	11.41	1.98×10^-12
B3GALT5	Beta-1， 3-galactosyltransferase 5	-2.44	2.47×10^-3	CELF3	CUGBP Elav-like family member 3	10.65	5.07×10^-10
SERPINB10	Serpin family B member 10	-2.42	3.81×10^-3	SLC17A6	Solute carrier family 17 member 6	10.23	3.61×10^-10
SERPINB4	Serpin family B member 4	-2.37	1.01×10^-2	OR2I1P	Olfactory receptor family 2 subfamily I member 1 pseudogene	10.20	1.03×10^-7
CYP2F2P	Cytochrome P450 family 2 subfamily F member 2， pseudogene	-2.33	5.01×10^-3	DPP6	Dipeptidyl peptidase like 6	10.11	1.68×10^-8
CYP2F1	Cytochrome P450 family 2 subfamily F member 1	-2.31	2.33×10^-5	CYP1A2	Cytochrome P450 family 1 subfamily A member 2	9.94	2.83×10^-9
ATP12A	ATPase H⁺/K⁺ transporting non-gastric alpha2 subunit	-2.30	1.70×10^-3	OR4D9	Olfactory receptor family 4 subfamily D member 9	9.92	2.16×10^-6
HORMAD1	HORMA domain containing 1	-2.26	3.05×10^-2	OR2T10	Olfactory receptor family 2 subfamily T member 10	9.89	2.41×10^-8
EDAR	Ectodysplasin A receptor	-2.23	2.02×10^-2	CPLX2	Complexin 2	9.82	4.16×10^-9
PTPRH	Protein tyrosine phosphatase receptor type H	-2.23	1.89×10^-2	OR2V2	Olfactory receptor family 2 subfamily V member 2	9.81	1.32×10^-9
AL512274.1	Homo sapiens chromosome 6 clone RP11-7K24	-2.14	2.18×10^-2	GFY	Golgi associated olfactory signaling regulator	9.78	4.25×10^-7
FOXQ1	Forkhead box Q1	-2.09	9.28×10^-3	OR2B11	Olfactory receptor family 2 subfamily B member 11	9.75	6.00×10^-5
AC044893.1	Homo sapiens chromosome 8 clone RP11-696E24 map 8， LOW-PASS SEQUENCE SAMPLING	-2.06	6.04×10^-3	FSTL5	Follistatin like 5	9.59	3.49×10^-53
KLK11	Kallikrein related peptidase 11	-2.02	2.80×10^-2	OR4E1	Olfactory receptor family 4 subfamily E member 1	9.56	6.86×10^-7
TMPRSS4	Transmembrane serine protease 4	-2.01	1.40×10^-2	OR4K17	Olfactory receptor family 4 subfamily K member 17	9.55	2.12×10^-7
				ZAN	Zonadhesin	9.52	1.25×10^-7
				SLC24A2	Solute carrier family 24 member 2	9.47	5.07×10^-10

新型冠状病毒（SARS-COV-2）感染后人嗅觉神经上皮细胞的基因组调控网络研究

Genomic regulatory network of human olfactory neuroepithelial cells infected with novel coronavirus (SARS-COV-2)

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