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Gene & Protein in Disease lncRNAs in trained immunity

H3K27Ac is gradually lost over time. This long-lived lncRNAs underscores their significance in orchestrating
accumulation of H3K4me3 is essential for the establishment the complexity of gene regulation within eukaryotic cells.
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of epigenetic memory, contributing to a sustained and Eukaryotic gene expression is regulated by the positioning
effective immunological response upon reexposure to the of nucleosomes, which are fundamental units of chromatin
same pathogen. In a related context, the lncRNA HOTTIP consisting of DNA wrapped around four core histone
has been noted to function epigenetically, regulating the proteins (H2A, H2B, H3, and H4). The interaction between
expression of homeotic genes during development. This histone cores and DNA significantly influences DNA
highlights the diverse roles of lncRNAs in epigenetic accessibility. Chromatins exhibit distinct modifications to
regulation across different biological processes. In a histones post-translationally, depending on whether they
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separate study, the expression of the lncRNA UMLILO are transcriptionally active or silent. In actively transcribed
was found to exhibit a positive correlation with the genes, specific modifications are commonly found. These
accumulation of histone modification H3K4me3 on the include high levels of lysine acetylation on the tails of H3
promoter of the CXCL gene. This observation suggests a and H4, trimethylation of H3 lysine 4, trimethylation of
potential role for UMLILO in mediating the regulation H3 lysine 79, ubiquitylation of H2B, and trimethylation of
of the H3K4me3 chromatin establishment mechanism H3 lysine 36. Conversely, repressed genes are associated
during trained immunity. The interplay between lncRNAs with modifications such as trimethylation of lysine 27,
and histone modifications further emphasizes the intricate ubiquitylation of H2A on lysine 119, and trimethylation
regulatory networks involved in shaping the epigenetic of H3 lysine 9. These post-translational modifications to
landscape during immune responses and trained histones contribute to the dynamic regulation of chromatin
immunity. The emerging role of lncRNAs in acquiring structure, reflecting the transcriptional status of genes
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epigenetic memory underscores their potential as novel in eukaryotic cells. 79,80 Growing evidence suggests that
drug targets for the development of the next generation of lncRNA can control the genome activity at the chromatin
immunotherapies. The intricate involvement of lncRNAs level. 80
in epigenetic regulation presents an opportunity to It has long been assumed that lncRNAs interact with
manipulate these molecules for therapeutic purposes, RNA, DNA, and proteins to modulate gene expression.
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especially in the context of immune memory and In addition, depending on the spatial organization of
responses. Figure 3 and Table 2 summarize lncRNAs with chromatin, lncRNA activity can be directed to certain
their epigenetic functions. loci. 31,65 As a result, the combination of nuclear architecture
and lncRNA activity can modulate immune gene
3.2. lncRNAs’ target chromatin structure transcription in a spatially dependent manner.
The regulation of gene expression is a highly intricate and
compartmentalized process in eukaryotes. lncRNAs play a 3.3. lncRNAs-guided genome targeting through
pivotal role in influencing numerous essential processes. chromosome looping
These include chromatin remodeling, recruitment of the In eukaryotes, the folding of DNA into chromosomal
transcription machinery, modulation of mRNA processing loops plays a pivotal role. These loops, formed within the
and cytoplasmic distribution, regulation of mRNA stability, nucleus, facilitate transcription by bringing co-regulated
control of translation, and involvement in posttranslational genes and enhancer-promoter elements into close spatial
activities, among others. The multifaceted impact of proximity, both in cis and trans configurations. Cis-acting

Table 2. LncRNAs in epigenetic regulation
lncRNA Function References
HOTTIP Bind with WDR5 and regulate the H3K4 methylation at the IFN gene locus. 84
NeST Bind with WDR5 and regulate the H3K4 methylation at the IFN gene locus. 85
UMLILO Directly interacting with the WDR5/MLL complex regulates the H3K4 methylation at the IFN gene locus. 76
XIST Formation of repressive chromatin. 74
MALAT1 Associated with an augmented deposition of H3K27me3 at genes linked to memory cells, facilitated 75
through direct interaction with EZH2.
RP5‑998N21.4 Boosts immune defense by binding to promoter regions and exerting influence on histone modifications. 72
TH2LCRR H3K4me3 is added to the promoters of T helper-2 cell cytokines, such as IL-4, IL-5, and IL-13. 77
Abbreviations: IL-5: Interleukin-5; LncRNAs: Long non-coding RNAs.

Volume 3 Issue 2 (2024) 9 doi: 10.36922/gpd.2791