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Long noncoding RNA MIR4435-2HG enhances metabolic function of myeloid dendritic cells from HIV-1 elite controllers
Ciputra Adijaya Hartana, … , Mathias Lichterfeld, Xu G. Yu
Ciputra Adijaya Hartana, … , Mathias Lichterfeld, Xu G. Yu
Published May 3, 2021
Citation Information: J Clin Invest. 2021;131(9):e146136. https://doi.org/10.1172/JCI146136.
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Research Article AIDS/HIV Immunology

Long noncoding RNA MIR4435-2HG enhances metabolic function of myeloid dendritic cells from HIV-1 elite controllers

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Abstract

Restriction of HIV-1 replication in elite controllers (ECs) is frequently attributed to T cell–mediated immune responses, while the specific contribution of innate immune cells is less clear. Here, we demonstrate an upregulation of the host long noncoding RNA (lncRNA) MIR4435-2HG in primary myeloid dendritic cells (mDCs) from ECs. Elevated expression of this lncRNA in mDCs was associated with a distinct immunometabolic profile, characterized by increased oxidative phosphorylation and glycolysis activities in response to TLR3 stimulation. Using functional assays, we show that MIR4435-2HG directly influenced the metabolic state of mDCs, likely through epigenetic mechanisms involving H3K27ac enrichment at an intronic enhancer in the RPTOR gene locus, the main component of the mammalian target of rapamycin complex 1 (mTORC1). Together, these results suggest a role of MIR4435-2HG for enhancing immunometabolic activities of mDCs in ECs through targeted epigenetic modifications of a member of the mTOR signaling pathway.

Authors

Ciputra Adijaya Hartana, Yelizaveta Rassadkina, Ce Gao, Enrique Martin-Gayo, Bruce D. Walker, Mathias Lichterfeld, Xu G. Yu

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Figure 9

MIR4435-2HG influences RPTOR expression in mDCs through H3K27ac histone modification.

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MIR4435-2HG influences RPTOR expression in mDCs through H3K27ac histone...
(A) Heatmap displaying genomic loci with significant (FDR-adjusted P value < 0.05) H3K27ac enrichment in ECs (n = 4) vs. HIVNs (n = 4). (B) Volcano plot showing H3K27ac-enriched genomic loci in ECs vs. HIVNs. Red dots represent data with –log (P value) > 1.3 and log2 fold change > 1. (C) Venn diagram showing overlap between H3K27ac-enriched regions in mDCs from ECs, genomic locations susceptible to MIR4435-2HG–dependent triple-helix formation predicted by TDF, and DEGs distinguishing mDCs treated with MIR4435-2HG siRNA vs. scramble siRNA. (D) CUT&RUN-Seq reads for H3K27ac, H3K27me3, and H3K4me3 at the RPTOR gene locus in ECs (n = 4) vs. HIVNs (n = 4). Yellow region marks an intronic enhancer region with significantly increased H3K27ac reads and gray region highlights the TDF-predicted MIR4435-2HG binding site. (E) The enrichment score for H3K27ac CUT&RUN-Seq reads in the intronic enhancer region of the RPTOR gene was compared between ECs and HIVNs. Mann Whitney U test was used as the statistical test. (F) Correlation analysis between MIR4435-2HG lncRNA and RPTOR mRNA expressions after normalization to ACTB in mDCs from ECs (n = 8). Pearson test was used to analyze the correlation. (G) The relative expression of RPTOR mRNA normalized to ACTB in mDCs from ECs (n = 8) nucleofected with either MIR4435-2HG siRNA or scramble siRNA for 48 hours was measured by RT-PCR. Wilcoxon matched pairs signed rank test was used as the statistical test. (H) The MFI of RPTOR protein expression in mDCs from EC (n = 8) nucleofected with either MIR4435-2HG siRNA or scramble siRNA for 48 hours was measured by flow cytometry. Wilcoxon matched pairs signed rank test was used as the statistical test. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.

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