Transcriptional Landscape of Enhancer RNAs in Peripheral Blood Mononuclear Cells from Patients with Systemic Lupus Erythematosus

Gangqiang Guo; Huijing Wang; Xinya Tong; Lele Ye; Xinyu Shi; Su Fang; Ya Hu; Fei Han; Chaosheng Chen; Ning Ding; Bofeng Su; Xiangyang Xue; Huidi Zhang

doi:10.2147/JIR.S331188

Transcriptional Landscape of Enhancer RNAs in Peripheral Blood Mononuclear Cells from Patients with Systemic Lupus Erythematosus

J Inflamm Res. 2022 Feb 4:15:775-791. doi: 10.2147/JIR.S331188. eCollection 2022.

Authors

Gangqiang Guo^#¹, Huijing Wang^#², Xinya Tong^#¹, Lele Ye¹, Xinyu Shi¹, Su Fang¹, Ya Hu³, Fei Han², Chaosheng Chen³, Ning Ding¹, Bofeng Su³, Xiangyang Xue¹, Huidi Zhang³

Affiliations

¹ Wenzhou Collaborative Innovation Center of Gastrointestinal Cancer in Basic Research & Precision Medicine, Wenzhou Key Laboratory of Cancer-Related Pathogens & Immunity, Department of Microbiology and Immunology, Institute of Molecular Virology and Immunology, Institute of Tropical Medicine, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, 325035, People's Republic of China.
² Kidney Disease Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, People's Republic of China.
³ Department of Nephrology, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, 325000, People's Republic of China.

^# Contributed equally.

Abstract

Objective: Enhancer RNAs (eRNAs), a class of non-coding RNAs, play indispensable roles in regulating target gene transcription and maintaining cell identity in cooperation with promoters. In this study, we investigated the transcriptional landscape and potential functions of eRNAs in peripheral blood mononuclear cells (PBMCs) from patients with systemic lupus erythematosus (SLE).

Methods: PBMCs from five patients with stable SLE, five patients with active SLE, and ten healthy individuals (HCs) were subjected to RNA-sequencing. Putative regulators, differential expression, and pathways were analyzed. eRNAs that were significantly upregulated were first validated by RT-qPCR in 12 samples. Then, candidate eRNAs were confirmed in a validation cohort of 45 samples. We conducted comprehensive pathway analyses to explore the correlations between the candidate eRNAs and SLE pathology.

Results: By analyzing eRNA transcript data from PBMCs from SLE patients and HCs, we identified various eRNAs and functional super-enhancers potentially related with SLE. The SLE-specificity of eRNAs seemed to be largely driven by SLE-specific transcription factors (TFs). A Venn diagram of eRNAs differentially expressed in stable, active, and total SLE vs HCs revealed that 13 and 23 eRNAs were commonly upregulated and downregulated, respectively, in patients with stable SLE and those with active SLE. The commonly upregulated eRNAs participate in regulating SLE-related pathways. Only eRNA TCONS_00034326 was significantly (P < 0.05) upregulated in PBMCs of patients with SLE when compared with those of HCs as indicated by RT-qPCR. The area under the receiver-operating curve of TCONS_00034326 for distinguishing SLE patients from HCs was 0.691. Through its putative SLE-related master TF, TCONS_00034326 is involved in multiple SLE-relevant signaling pathways, especially tumor necrosis factor signaling.

Conclusion: This study unraveled the transcriptional landscape of eRNAs, eRNA-related TFs, and super-enhancers in PBMCs from SLE patients and HCs. We identified a panel of SLE-relevant eRNAs, providing potential targets in SLE pathogenesis.

Keywords: PBMCs; SLE; TFs; eRNA; enhancer RNA; super-enhancer; systemic lupus erythematosus; transcription factors.

Grants and funding

This study was supported by National Nature Science Foundation of China (grant No. 82001705), Zhejiang Provincial Natural Science Foundation of China (grant No. LY20H100003), Medical Health Science and Technology Project of Zhejiang Provincial Health Commission (grant No. 2019KY453), Wenzhou Municipal Science and Technology Bureau (grant No.Y20210089; No. Y20180158).