IL-4 Inhibits the Biogenesis of an Epigenetically Suppressive PIWI-Interacting RNA To Upregulate CD1a Molecules on Monocytes/Dendritic Cells
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Xue Zhang1, Xin He1, Chao Liu1
1Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, China; Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, China; and Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, China.
Abstract:
The discovery of PIWI-interacting RNAs (piRNAs) revealed the complexity of the RNA world. Although piRNAs were first deemed to be germline specific, substantial evidence shows their various roles in somatic cells; however, their function in highly differentiated immune cells remains elusive. In this study, by initially screening with a small RNA deep-sequencing analysis, we found that a piRNA, tRNA-Glu-derived piRNA [td-piR(Glu)], was expressed much more abundantly in human monocytes than in dendritic cells. By regulating the polymerase III activity, IL-4 potently decreased the biogenesis of tRNA-Glu and, subsequently, td-piR(Glu). Further, we revealed that the td-piR(Glu)/PIWIL4 complex recruited SETDB1, SUV39H1, and heterochromatin protein 1β to the CD1A promoter region and facilitated H3K9 methylation. As a result, the transcription of CD1A was significantly inhibited. Collectively, we demonstrated that a piRNA acted as the signal molecule for a cytokine to regulate the expression of an important membrane protein for lipid Ag presentation.
Insights
A novel PIWI-interacting RNA (piRNA), td-piR(Glu), regulates CD1A gene expression in human monocytes. Interleukin-4 (IL-4) reduces td-piR(Glu) levels, impacting lipid antigen presentation.
Area of Science:
- * Molecular Biology
- * Immunology
- * Epigenetics
Background:
- * PIWI-interacting RNAs (piRNAs) are crucial regulators, initially thought to be germline-specific but now recognized for somatic roles.
- * The function of piRNAs in differentiated immune cells, particularly monocytes and dendritic cells, remains largely unexplored.
- * CD1A is a key membrane protein involved in lipid antigen presentation.
Purpose of the Study:
- * To investigate the role of piRNAs in human monocytes and dendritic cells.
- * To elucidate the mechanism by which a specific piRNA, tRNA-Glu-derived piR [td-piR(Glu)], influences immune cell function.
- * To determine the impact of cytokine signaling on piRNA biogenesis and gene regulation in immune cells.
Main Methods:
- * Small RNA deep-sequencing analysis to identify differentially expressed piRNAs in monocytes versus dendritic cells.
- * Investigation of Interleukin-4 (IL-4) effects on tRNA-Glu and td-piR(Glu) biogenesis via polymerase III activity.
- * Chromatin immunoprecipitation followed by sequencing (ChIP-seq) to assess protein complex recruitment to the CD1A promoter and H3K9 methylation levels.
Main Results:
- * A tRNA-Glu-derived piRNA [td-piR(Glu)] was found to be significantly more abundant in human monocytes compared to dendritic cells.
- * IL-4 treatment decreased tRNA-Glu and td-piR(Glu) biogenesis by regulating polymerase III activity.
- * The td-piR(Glu)/PIWIL4 complex recruited epigenetic modifiers (SETDB1, SUV39H1, HP1β) to the CD1A promoter, leading to H3K9 methylation and CD1A transcriptional inhibition.
Conclusions:
- * A specific piRNA, td-piR(Glu), acts as a molecular signal linking cytokine stimulation (IL-4) to gene expression changes in immune cells.
- * This piRNA-mediated epigenetic mechanism regulates the transcription of CD1A, a critical protein for lipid antigen presentation.
- * The study reveals a novel piRNA-dependent pathway in immune cell differentiation and function, highlighting piRNAs' role beyond the germline.
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