Long noncoding RNA MIR4435-2HG enhances metabolic function of myeloid dendritic cells from HIV-1 elite controllers
Ciputra Adijaya Hartana, Yelizaveta Rassadkina, Ce Gao, Enrique Martin-Gayo, Bruce D. Walker, Mathias Lichterfeld, Xu G. Yu
Ciputra Adijaya Hartana, Yelizaveta Rassadkina, Ce Gao, Enrique Martin-Gayo, Bruce D. Walker, Mathias Lichterfeld, Xu G. Yu
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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

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 1

Increased expression of lncRNA MIR4435-2HG in primary mDCs from ECs.

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Increased expression of lncRNA MIR4435-2HG in primary mDCs from ECs. (A)...
(A) Heatmap displaying differentially expressed lncRNAs (FDR-adjusted P value < 0.05) in mDCs from ECs (n = 20) vs. HIVNs (n = 15) and HAARTs (n = 13) measured by RNAseq. (B) The expression (TPM+1) of MIR4435-2HG in mDCs was compared among ECs (n = 20), HIVNs (n = 15), and HAARTs (n = 13). Kruskal-Wallis test was used as the statistical test. (C) Venn diagram showing overlap between genes differentially expressed (FDR-adjusted P value < 0.0001) between EC vs. HIVN and EC vs. HAART and correlated with MIR4435-2HG expression (FDR-adjusted correlation P value < 0.0001). (D) Canonical pathways predicted to be significantly enriched for 924 DEGs from C, using IPA. Pathways predicated to be activated or inhibited are highlighted in red or blue, respectively. Pathways with no predicted change are marked in gray. Cutoff was established at –log (P value) ≥ 2 (yellow dashed line) and z score > 1.5 or < –1.5. (E) Heatmaps displaying DEGs involved in oxidative phosphorylation or mTOR signaling predicted by IPA in D (FDR-adjusted P value < 0.05).