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. 2022 Mar 15:9:798907.
doi: 10.3389/fmed.2022.798907. eCollection 2022.

Sexual Dimorphisms of Protein-Coding Gene Profiles in Placentas From Women With Systemic Lupus Erythematosus

Hui-Hui Li  1   2 , Lin-Tao Sai  3 , Shan Tian  4 , Yuan Liu  1 , Colman I Freel  2 , Kai Wang  5 , Chi Zhou  6 , Jing Zheng  2 , Qiang Shu  7   8 , Ying-Jie Zhao  7   8
Affiliations

Sexual Dimorphisms of Protein-Coding Gene Profiles in Placentas From Women With Systemic Lupus Erythematosus

Hui-Hui Li et al. Front Med (Lausanne). .

Abstract

Background: Systemic lupus erythematosus (SLE) may cause pathogenic changes in the placentas during human pregnancy, such as decreased placental weight, intraplacental hematoma, ischemic hypoxic change, placental infarction, and decidual vasculopathy, which contribute to high maternal and fetal mortality and morbidity. Sex-specific adaptations of the fetus are associated with SLE pregnancies. The present study aimed to determine the transcriptomic profiles of female and male placentas from women with SLE.

Methods: RNA sequencing (RNA-seq) was performed to identify differentially expressed protein-coding genes (DEGs) in placentas from women with SLE vs. normal term (NT) pregnancies with female and male fetuses (n = 3-5/sex/group). Real-time-quantitative PCR was performed (n = 4 /sex/group) to validate the RNA-seq results. Bioinformatics functional analysis was performed to predict the biological functions and pathways of SLE-dysregulated protein-coding genes.

Results: Compared with NT-female (NT-F) placentas, 119 DEGs were identified in SLE-female (SLE-F) placentas. Among these 119 DEGs, five and zero are located on X- and Y-chromosomes, respectively, and four are located on the mitochondrial genome. Compared with NT-male (NT-M) placentas, 458 DEGs were identified in SLE-male (SLE-M) placentas, among which 16 are located on the X-chromosome and zero on the Y-chromosome and mitochondrial genome. Twenty-four DEGs were commonly dysregulated in SLE-F and -M placentas. Functional analysis showed that SLE-dysregulated protein-coding genes were associated with diverse biological functions and pathways, including angiogenesis, cellular response to growth factor stimulus, heparin-binding, HIF (hypoxia-inducible factor)-1 signaling pathway, and Interleukin-17 (IL-17) signaling pathway in both SLE-F and -M placentas. Biological regulations were differentially enriched between SLE-F and -M placentas. Regulation of blood circulation, response to glucocorticoid, and rhythmic process were all enriched in SLE-F, but not SLE-M placentas. In contrast, tumor necrosis factor production, Th17 cell differentiation, and MDA (melanoma differentiation-associated gene)-5 signaling pathway were enriched in SLE-M but not SLE-F placentas.

Conclusion: This report investigated the protein-coding gene profiles of placenta tissues from SLE patients using RNA-seq. The results suggest that the SLE-dysregulated protein-coding genes in placentas may contribute to the pathophysiological progress of SLE pregnancies in a fetal sex-specific manner, leading to adverse pregnancy outcomes.

Keywords: fetal sex; placenta; pregnancy; protein-coding RNA; systemic lupus erythematosus.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
SLE differentially dysregulates transcriptomic profiles of female and male placentas. (A) Circos plot illustrating the chromosome location of differentially expressed protein-coding genes between SLE-F vs. NT-F (pink dots) and SLE-M vs. NT-M (blue dots). Each dot represents one differentially expressed gene. The letters and numbers in the outer layer represent the chromosome location. For the scatter plot tracks, dots outside and inside of the centerline represent upregulated and downregulated genes, respectively. (B,C) Volcano plots showing differentially expressed genes between SLE-F vs. NT-F, and SLE-M vs. NT-M in RNA-seq. Gray dots: no significant difference; pink and green dots: > two-fold upregulation and downregulation, respectively (FDR-adjusted P-value < 0.05) in SLE vs. NT; n = 3-5/group. (D,E) RT-qPCR validation of SLE-dysregulated genes in female and male placentas. *P < 0.05 vs. NT, n = 4/group. MT, mitochondrial DNA; SLE, systemic lupus erythematosus; APOLD1, apolipoprotein L domain containing 1; C3, complement C3; CTGF, connective tissue growth factor; DUSP1, dual specificity phosphatase 1; GH2, growth hormone 2; PLAC1, placenta specific 1; FN1, fibronectin 1; PSG4, pregnancy-specific beta-1-glycoprotein 4; VEGFA, vascular endothelial growth factor A; MMP1, matrix metallopeptidase 1. RNA-seq, RNA sequencing; FDR, false discovery rate. Circos plot showing the location DE-genes was generated using circa software for Windows.
Figure 2
Figure 2
Enrichment analysis of dysregulated protein-coding genes in SLE-F and -M placentas. (A) Commonly enriched GOs terms from both SLE-F and -M placentas. (B) Un-commonly enriched GO terms from SLE-F and -M placentas, respectively. (C) Commonly enriched KEGG terms from both SLE-F and -M placentas. (D) Un-commonly enriched KEGG terms from SLE-F and -M placentas, respectively. (E) Network of GO and KEGG enriched terms from SLE-F placentas colored by P-value, where terms containing more dysregulated genes indicate a more significant P-value. (F) Network of GO and KEGG enriched terms from SLE-M placentas colored by P-value, where terms containing more genes tend to have a more significant P-value. SLE, systemic lupus erythematosus; F, female; M, male; GO, Gene Ontology; KEGG, Kyoto Encyclopedia of Genes and Genomes.
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