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

doi:10.3969/j.issn.1674-8115.2022.11.002

Abstract

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

CLC Number:

R183.3

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.

Figures/Tables 8

TrendMD

References 31

1	HUANG C L, WANG Y M, LI X W, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China[J]. Lancet, 2020, 395(10223): 497-506.
2	EASTIN C, EASTIN T. Clinical characteristics of coronavirus disease 2019 in China[J]. J Emerg Med, 2020, 58(4): 711-712.
3	CHEN N S, ZHOU M, DONG X, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study[J]. Lancet, 2020, 395(10223): 507-513.
4	WANG D W, HU B, HU C, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China[J]. JAMA, 2020, 323(11): 1061-1069.
5	YAN C H, FARAJI F, PRAJAPATI D P, et al. Association of chemosensory dysfunction and COVID-19 in patients presenting with influenza-like symptoms[J]. Int Forum Allergy Rhinol, 2020, 10(7): 806-813.
6	KUANG S H, CHARGÉ S B, SEALE P, et al. Distinct roles for Pax7 and Pax3 in adult regenerative myogenesis[J]. J Cell Biol, 2006, 172(1): 103-113.
7	RELAIX F, MONTARRAS D, ZAFFRAN S, et al. Pax3 and Pax7 have distinct and overlapping functions in adult muscle progenitor cells[J]. J Cell Biol, 2006, 172(1): 91-102.
8	SAITO H, KUBOTA M, ROBERTS RW, et al. RTP family members induce functional expression of mammalian odorant receptors[J]. Cell, 2004, 119(5): 679-691.
9	于腾. RTP1S与RTP2在辅助嗅觉受体功能性表达的过程中功能具有多样性[D]. 上海: 上海交通大学, 2017.
	YU T. RTP1S and RTP2 have diverse functions in assisting the functional expression of olfactory receptors[D]. Shanghai: Shanghai Jiao Tong University, 2017.
10	SONG J, MURAKAMI H, TSUTSUI H, et al. Genomic organization and expression of a human gene for myc-associated zinc finger protein (MAZ)[J]. J Biol Chem, 1998, 273(32): 20603-20614.
11	RAY A, RAY B K. Isolation and functional characterization of cDNA of serum amyloid A-activating factor that binds to the serum amyloid A promoter[J]. Mol Cell Biol, 1998, 18(12): 7327-7335.
12	RAY A, RAY B K. A novel Cis-acting element is essential for cytokine-mediated transcriptional induction of the serum amyloid A gene in nonhepatic cells[J]. Mol Cell Biol, 1996, 16(4): 1584-1594.
13	RAY A, DHAR S, RAY B K. Control of VEGF expression in triple-negative breast carcinoma cells by suppression of SAF-1 transcription factor activity[J]. Mol Cancer Res, 2011, 9(8): 1030-1041.
14	WANG X, SOUTHARD R C, ALLRED C D, et al. MAZ drives tumor-specific expression of PPAR gamma 1 in breast cancer cells[J]. Breast Cancer Res Treat, 2008, 111(1): 103-111.
15	JIAO L, LI Y, SHEN D, et al. The prostate cancer-up-regulated Myc-associated zinc-finger protein (MAZ) modulates proliferation and metastasis through reciprocal regulation of androgen receptor[J]. Med Oncol, 2013, 30(2): 570.
16	毛建国. MAZ介导的自噬抑制在鼻咽癌转移中的作用和分子机制研究[D]. 西安: 第四军医大学, 2017.
	MAO J G. Role and molecular mechanism of MAZ-mediated autophagy inhibition in nasopharyngeal carcinoma metastasis[D]. Xi′an: Fourth Military Medical University, 2017.
17	JIA C M, TIAN Y Y, QUAN L N, et al. miR-26b-5p suppresses proliferation and promotes apoptosis in multiple myeloma cells by targeting JAG1[J]. Pathol Res Pract, 2018, 214(9): 1388-1394.
18	FAN F, LU J J, YU W L, et al. microRNA-26b-5p regulates cell proliferation, invasion and metastasis in human intrahepatic cholangiocarcinoma by targeting S100A7[J]. Oncol Lett, 2018, 15(1): 386-392.
19	TANG C M, ZHANG M, HUANG L, et al. CircRNA_000203 enhances the expression of fibrosis-associated genes by derepressing targets of miR-26b-5p, Col1a2 and CTGF, in cardiac fibroblasts[J]. Sci Rep, 2017, 7: 40342.
20	谢蒙. Hsa-miR-26b-5p在硬皮病中的生物信息学分析和功能研究[D]. 武汉: 华中科技大学, 2019.
	XIE M. Bioinformatics analysis and functional study of HSA-Mir-26b-5p in scleroderma [D]. Wuhan: Huazhong University of Science and Technology, 2019.
21	UniProt.UniProtKB-Q14332(FZD2_HUMAN)[EB/OL].(2021.7.12)[2021.7.12].http://www.uniprot.org/uniprot/Q14332#function.
22	董少婷. TRIB3基因的研究进展[J]. 中国基层医药, 2016, 23(4): 625-627.
	DONG S T. Research progress of TRIB3 gene[J]. China Prim Med, 2016, 23(4):625-627.
23	YOKOYAMA T, NAKAMURA T. Tribbles in disease: signaling pathways important for cellular function and neoplastic transformation[J]. Cancer Sci, 2011, 102(6): 1115-1122.
24	UniProt.UniProtKB-O15075(DCLK1_HUMAN)[EB/OL].(2021.7.12)[2021.7.12].http://www.uniprot.org/uniprot/O15075#function.
25	SIDDHARTA A, PFAENDER S, VIELLE NJ, et al. Virucidal activity of World Health Organization-recommended formulations against enveloped viruses, including zika, Ebola, and emerging coronaviruses[J]. J Infect Dis, 2017, 215(6): 902-906.
26	BARR T, HELMS C, GRANT K, et al. Opposing effects of alcohol on the immune system[J]. Prog Neuropsychopharmacol Biol Psychiatry, 2016, 65: 242-251.
27	SZABO G, SAHA B. Alcohol′s effect on host defense[J]. Alcohol Res, 2015, 37(2): 159-170.
28	THE LANCET GASTROENTEROLOGY & HEPATOLOGY. Drinking alone: covid-19, lockdown, and alcohol-related harm[J]. Lancet Gastroenterol Hepatol, 2020, 5(7): 625.
29	UniProt.UniProtKB-A5X5Y0(5HT3E_HUMAN)[EB/OL].(2021.7.12)[2021.7.12].http://www.uniprot.org/uniprot/O15075#function.
30	GeneCards.CHRNB2-Gene[EB/OL].(2021.7.12) [2021.7.12].https://www.genecards.org/cgi-bin/carddisp.pl?gene=CHRNB2#function.
31	GeneCards.KCNJ9-Gene[EB/OL].(2021.7.12) [2021.7.12].https://www.genecards.org/cgi-bin/carddisp.pl?gene=KCNJ9#function.

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

[1]	YANG Wenqian, CHEN Chiqi, ZHAO Lu, CAO Liyuan, XIA Yiqiu, LU Zhigang, ZHENG Junke. Immune inhibitory receptor LILRB2 enhances SARS-CoV-2 spike protein-mediated immune inflammation [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2022, 42(9): 1188-1196.
[2]	JIANG Gan, YANG Yuquan, CHEN Yaoxing, HOU Zhaoyuan, GAO Xiaoling, CHEN Hongzhuan, JIA Hao. Preliminary study on the cellular level of SARS-CoV-2 proteins mediated by macropinocytosis pathway [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2022, 42(8): 987-996.
[3]	Jia-qiang LUO, Liang-yu ZHAO, Chen-cheng YAO, Zi-jue ZHU, Xiao-yu XING, Peng LI, Ru-hui TIAN, Hui-xing CHEN, Jie SUN, Zheng LI. Single-cell RNA sequencing reveals the spatio-temporal expression profile of SARS-CoV-2 related receptor in human and mouse testes [J]. JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE), 2021, 41(4): 421-426.
[4]	Jiang YUE, Yong ZHOU, Hua XU, Wen LIU, Xiao-feng HAN, Qing MAO, Ji-dong ZHANG, Jing MA, Han-dong JIANG, Wei LIU. Characteristic analysis and comparison of glycolipid metabolism in patients with coronavirus disease 2019 in common condition and severe cases [J]. JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE), 2021, 41(3): 355-359.
[5]	Xiao-ya LÜ, Lei SONG, Zhao MA, Shu-guang WANG, Hao MA, Yi-ming SHAO, Zhi-yin WU. Strengthening and optimization of immunization strategy for COVID-19 vaccines [J]. JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE), 2021, 41(12): 1545-1550.
[6]	Jing TAO, Qing-zhi ZENG, Jin DANG, Jian-yin QIU. Reliability and Validity of Corona Virus Disease 2019 (COVID-19) Peritraumatic Distress Index (CPDI) [J]. JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE), 2021, 41(10): 1359-1365.
[7]	SHI Da-ke, HU Wei-guo, YANG Zhi-tao, LIN Jing-sheng, WANG Xiao-ning, GUO Ying, QIAN Wen-jing, CAI Ming, XIANG Xiao-gang, LIANG Xiao-hong, ZHAI Rong-cheng, ZHANG Yi-bo, NI Yu-Xing. Experience of healthcare-acquired infection control against coronavirus disease 2019 by integrated medical team in Wuhan [J]. JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE), 2020, 40(8): 1009-1012.
[8]	ZHA Qiong-fang1, LI Hong-bo2, QIN Hui1. Research progress of interaction between coronavirus disease 2019 and cardiovascular system [J]. JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE), 2020, 40(7): 863-866.
[9]	HU Cheng-fang1, 2, ZHU Jie1, LUO Li 2, 3, CAO Jian-wen2, 4, TAO Min-fang2, 5. Analysis of emergency management measures in large public hospitals during corona virus disease 2019 epidemic prevention [J]. JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE), 2020, 40(7): 867-872.
[10]	QU Tian-tian1, 2, FENG Tie-nan1, 2, JIANG Jia-yuan1, 2, ZHANG Fan1, 2, QIAN Bi-yun1, 2. Analysis and consideration of registration information of global coronavirus disease 2019 clinical study [J]. JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE), 2020, 40(6): 707-712.
[11]	LI Qiang1, 2, SUN Zhe2, QIAN Bi-yun2, 3, FENG Tie-nan2, 4. Retrospective analysis of Chinese epidemic situation model based on elbow cluster analysis [J]. JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE), 2020, 40(6): 713-718.
[12]	QIU Cheng-hao1, LU Hong-zhou2, SONG Bing3, LING Yun2, LIU Xin-zhe1, ZHU Ting-ting1. Analysis of clinical features and related factors of coronavirus disease 2019 in Shanghai [J]. JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE), 2020, 40(5): 559-565.
[13]	LIN Mao-wen, LIU Tian, TIAN Ke-qing, JIANG Hong, ZENG Min-min, WANG Li, YIN Jun, LEI Ruo-qian, YAO Meng-lei, HUANG Ji-gui. Spatial-temporal distribution of coronavirus disease 2019 in Jingzhou City [J]. JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE), 2020, 40(5): 566-572.
[14]	YANG Zhi-tao, GAO Wei-yi, LIANG Jing, JING Feng, MAO En-qiang, CHEN Er-zhen. Experience of emergency department of large tertiary general hospital in coping with epidemic outbreak of COVID-19 [J]. , 2020, 40(4): 417-.
[15]	HE Hao, HE Yun-ting, ZHAI Jing, WANG Xiao-jin, WANG Bing-shun. Predicting the trend of the COVID-19 outbreak and timely grading the current risk level of epidemic based on moving average prediction limits [J]. , 2020, 40(4): 422-.