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Gene & Protein in Disease lncRNAs in trained immunity

lncRNAs exert their influence at the site of transcription, specifically IPLs, in orchestrating chromosomal contacts
impacting the expression of nearby genes. Conversely, and facilitating epigenetic priming of immune genes as
trans-acting lncRNAs operate at a distance from the part of the mechanism underlying trained immunity. 81,82
synthesis site. The chromatin organization extends to lncRNAs have also been identified as key regulators of toll-
domains enriched in chromosomal loops, known as like receptors (TLR) signaling and innate immunity. 86,87
topologically associating domains (TADs), contributing For example, the LPS-sensitive lncRNA Mirt2 is expressed
significantly to the three-dimensional architecture of the in macrophages and inhibits TLR4 signaling by inhibiting
genome. The TADs play a crucial role in shaping the spatial NF-κB and MAPK activation and subsequent TNF
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arrangement of genes and regulatory elements within generation (Table 2).
the eukaryotic nucleus, ensuring proper gene regulation In the field of trained immunity, a central question
and coordination of transcriptional activities. Indeed, that remains to be answered is the mechanism by which
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evidence has shown that lncRNAs play a role in mediating epigenetic marks are precisely deposited at specific
the assembly of TADs. Enhancer RNAs (eRNAs), a loci, particularly at the promoters of trained genes.
specific class of lncRNAs, are synthesized from active Understanding the molecular processes and regulatory
enhancer regions and contribute to the regulation of gene factors involved in the discrete deposition of epigenetic
expression. One of the functions of eRNAs is to facilitate marks is crucial for unraveling the intricacies of trained
chromatin looping between enhancers and promoters immunity and its underlying mechanisms. This includes
during the transcription process. This dynamic interplay elucidating the roles of various molecular players, such
involving lncRNAs, particularly eRNAs, adds another as lncRNAs, chromatin-modifying complexes, and
layer of complexity to the regulation of gene expression. other epigenetic regulators, in orchestrating the targeted
By participating in the spatial organization of chromatin establishment of epigenetic marks at specific genomic
and the formation of chromosomal loops, lncRNAs loci. Further research in this area is essential for gaining
contribute to the intricate orchestration of transcriptional comprehensive insights into the molecular basis of trained
activities within the eukaryotic genome. 16,82,83 In addition, immunity and advancing our ability to modulate immune
certain lncRNAs are involved in remodeling the chromatin responses for therapeutic purposes. Evidence suggests
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complex and catalyzing the trimethylation of histone H3 at that metabolic changes serve as the principal initiators,
lysine 4 (H3K4me3) on the promoters of target genes. For supplying the necessary substrates and co-factors crucial
instance, HOTTIP, a lncRNA transcribed from the HOXA for epigenetic reprogramming. However, despite the
locus, and NeST lncRNA directly interact with WD repeat- widespread presence of these accumulated substrates
containing protein 5 (WDR5), influencing the modulation and co-factors throughout cells, evidence suggests the
of H3K4me at specific gene loci such as the IFN gene existence of specialized machinery within the nucleus that
locus. This interaction highlights the role of lncRNAs in orchestrates targeted epigenetic changes, as depicted in
regulating histone modifications and chromatin structure, Figure 3.
contributing to the precise control of gene expression. 84,85
In a study conducted by Fanucchi et al., the pivotal role 3.4. lncRNAs role in metabolic alterations
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of lncRNAs in trained immunity was first demonstrated. A growing body of research suggests that metabolic alterations
The researchers identified a specific group of lncRNAs contribute to myeloid cell epigenetic reprogramming,
referred to as immune gene priming lncRNAs (IPLs leading to a trained immunological phenotype and non-
or IP-lncRNAs), which were found to be brought into specific resistance to secondary infection. Recently, various
proximity with immune genes before their activation, as lncRNAs such as lncRNA-p23154, lncRNA-NEF, HOTAIR,
revealed by chromatin 3D structure analysis. UMLILO, an and MACC1‑AS1 have been identified in association with
upstream master lncRNA of the inflammatory chemokine metabolic alterations, where they control GLUT1 for
locus, was employed as a representative IPL to validate the glucose absorption. In addition, lncRNAs ftx and SNHG3
findings. This IPL established chromosomal contacts with regulate the oxidative phosphorylation metabolic enzyme in
the ELR+ CXCL chemokines (IL-8, CXCL1, CXCL2, and cancer. Pathogens employ diverse strategies to manipulate
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CXCL3) and acted in cis to guide the WDR5–mixed lineage host cell metabolism, involving glutamine and glycolysis
leukemia protein 1 (MLL1) complex across the chemokine metabolism. Notably, lncRNAs like lncRNA-ACOD1 and
promoters. This facilitated the epigenetic priming of these lncRNA-HOTAIR have been implicated in the metabolic
promoters through H3K4me3 modification, preparing regulation of virus infection. In colorectal cancer, F.
them for active transcription. Notably, the regulation of nucleatum targets lncRNA enolase 1-intronic transcript 1 for
genes such as IL‑6 and IL‑1 followed a similar pattern. glycolysis. Inflammation triggers the dectin-1-Akt-mTOR-
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These findings highlight the critical role of lncRNAs, HIF-1 pathway to shift from oxidative phosphorylation to

Volume 3 Issue 2 (2024) 10 doi: 10.36922/gpd.2791