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Kamal et al. J Transl Genet Genom 2024;8:162-85 https://dx.doi.org/10.20517/jtgg.2023.55 Page 166

DNA methylation
DNA methylation can be considered a major epigenetic technique to alter the gene expression pattern for
any coding or non-coding gene. According to the CpG dinucleotide content of the genome, there are two
[32]
types of regions: low CpG regions and high CpG regions . Within CpG dinucleotides, DNA methylation
mainly occurs at the cytosine, and methylated cytosines often quickly mutate into thymines. Low CpG sites
are created when CpG dinucleotides degrade due to mutation after DNA hypermethylation. High CpG and
low CpG sites both represent hypomethylation and hypermethylation, respectively. Genes that are located
within the low CpG sites may have lower expression levels than genes that are present within the high CpG
[33]
sites because promoter hypermethylation often suppresses gene expression . Consequently, the lower
expression of lncRNAs may be explained by the fact that many lncRNA genes are located within low CpG
[29]
sites, and what also implicates this fact is the lower perseverance of H3K4me3 around those sites .
Transcriptional regulation
At the transcription level, the most diverse and not fully understood mechanism pertains to the regulation
of lncRNAs. One example is the shared transcription factors between some lncRNAs and protein-coding
genes. For instance, RP1-473L15.2 and ENST00000513542, two lncRNAs, possess motifs corresponding to
[34]
serum response factor and activating protein-1, respectively . Another example is a novel lncRNA related
to DNA damage known as AK019103, which, in its promoter region, exhibits five binding sites for the
[35]
transcription factor NF-κB . Additionally, core transcription factors such as p53, NF-κB, Sox2, Pou5f1, and
Nanog have been found to be sufficient for driving the expression of various lncRNAs across processes
[36]
ranging from embryonic stem cell pluripotency to cell proliferation . This phenomenon may, in part,
reflect the tissue and cell-type specificity inherent in lncRNAs, wherein simultaneous regulation of common
genes sharing the same transcription sites occurs in specific tissues and cells where these transcription sites
are specifically expressed.

MicroRNAs, a class of ncRNAs smaller in size than lncRNAs and capable of regulating the process of
gene expression of protein-coding genes, have also been found to be involved in the transcriptional
[29]
regulation of lncRNAs . For instance, miRNA-29 has been reported to enhance the expression of the
lncRNA MEG3 by inhibiting DNA methyltransferase and preventing methylation of MEG3's promoter .
[37]
Another interesting example involves miRNA-372, which has been found to regulate the expression of
the lncRNA HULC in liver cancer through its interaction with the cAMP Response Element-Binding
transcription factor . This indicates that regulatory control over lncRNAs is not exclusive to protein
[38]
transcription factors; instead, it also involves other factors and mechanisms that are specific to cells and
tissues.

Post-transcriptional regulation
Competitive endogenous RNA networks are intricate systems comprising microRNAs, pseudogenes,
protein-coding genes, and lncRNAs. These networks feature microRNA response elements (MREs) and
engage in crosstalk, mutually influencing the expression and stability of each component interactively .
[39]
For instance, in human cancer cells, as a post-transcriptional regulatory mechanism, the repression of the
lncRNA HOTAIR by miRNA-141 occurs in the presence of the Argonaut 2 (AGO-2) complex . In another
[40]
study, it was shown that the degradation of the lncRNA HOTAIR involves a collaborative action of miRNA-
let7i, HuR, and AGO-2 . Moreover, a study led by Han et al. verified that during the development of
[41]
bladder cancer, the lncRNA MALAT1 experienced downregulation mediated by has-miR-125b .
[42]