MiR302c, Sp1, and NFATc2 regulate interleukin‐21 expression in human CD4+CD45RO+ T lymphocytes

• Published in: Journal of cellular physiology Vol. 234; no. 5; pp. 5998 - 6011
• Main Authors: El‐Said, Hassan, Fayyad‐Kazan, Mohammad, Aoun, Rabab, Borghol, Nada, Skafi, Najwa, Rouas, Redouane, Vanhamme, Luc, Mourtada, Mohamad, Ezzeddine, Mohamad, Burny, Arsène, Fayyad‐Kazan, Hussein, Badran, Bassam
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.05.2019
• Subjects: 3' Untranslated Regions; Acetylation; Binding; Binding Sites; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; CD45RA antigen; CD45RO; Cytokines; Gene expression; Healthy Volunteers; HEK293 Cells; HeLa Cells; Histone H4; Histones - metabolism; Humans; Immune system; Interleukins; Interleukins - genetics; Interleukins - metabolism; interleukin‐21 (IL‐21); Jurkat Cells; Leukocyte Common Antigens - immunology; Leukocyte Common Antigens - metabolism; Lymphocytes; Lymphocytes T; microRNAs (miRNAs); MicroRNAs - genetics; MicroRNAs - metabolism; miRNA; Molecular modelling; NFATC Transcription Factors - genetics; NFATC Transcription Factors - metabolism; promoter; Promoter Regions, Genetic; Ribonucleic acid; RNA; Sp1 protein; Sp1 Transcription Factor - genetics; Sp1 Transcription Factor - metabolism; Transcription factors; Transcription Initiation Site; Transcription, Genetic; interleukin-21 (IL-21); promoter; CD45RO; microRNAs (miRNAs)
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.27151

Interleukin‐21 (IL‐21) is a cytokine with potent regulatory effects on different immune cells. Recently, IL‐21 has been contemplated for use in the treatment of cancers. However, the molecular mechanisms regulating human IL‐21 gene expression has not yet been described. In this study, we initially studied the promoter region and identified the transcription start site. We thereafter described the essential region upstream of the transcription start site and showed the in vivo binding of NFATc2 and SP1 transcription factors to this region, in addition to their positive role in IL‐21 expression. We also studied the role of microRNAs (miRNAs) in regulating IL‐21 expression. We, thus, established the miRNA profile of CD4+CD45RO+ versus CD4+CD45RA+ isolated from healthy volunteers and identified a signature composed of 12 differentially expressed miRNAs. We showed that miR‐302c is able to negatively regulate IL‐21 expression by binding directly to its target site in the 3′‐untranslated region. Moreover, after using fresh human CD4‐positive T cells, we observed the high acetylation level of histone H4, an observation well in line with the already described high expression of IL‐21 in CD4+CD45RO+ versus CD4+CD45RA+ T cells. Altogether, our data identified different molecular mechanisms regulating IL‐21 expression. We defined the promoter region of human interleukin‐21 (IL‐21) gene and identified different mechanisms, including Sp1 and NFATc2 transcription factors. Acetylation status of histones and miR‐302c is be involved in regulating the IL‐21 expression. These molecular mechanisms could, therefore, be targeted to manipulate IL‐21 expression in the context of disease treatment.