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Page 216 Bergara-Muguruza et al. J Transl Genet Genom 2023;7:213-229 https://dx.doi.org/10.20517/jtgg.2023.14

genome, lncRNAs can be intergenic (referred to as lincRNAs), or intronic when they are transcribed from
[2]
[2]
introns of protein-coding genes . lncRNAs locate on opposite DNA strands of a protein-coding gene and
[15]
are divergently transcribed or can overlap the DNA strand of a protein-coding gene, and thus, share
[2]
exons with it . Antisense lncRNAs are transcribed from the antisense strand of protein-coding genes ,
[2]
being the most abundant lncRNAs in mice and humans .
[20]
While significant progress has been made in mapping lncRNAs, elucidating their functional roles has been
challenging. There is increasing evidence that specific secondary structure and protein binding motifs of
lncRNAs are key for their function; however, we are far from being able to predict the function of a lncRNA
from these characteristics [15,16,19] . lncRNAs are able to interact with DNA, multiple proteins, or other RNA
molecules, making them good candidates for scaffolding functions and gene regulation . Indeed, lncRNA
[21]
molecules are involved in various cellular processes and the list of roles that they accomplish is continuously
expanding .
[9]
Most lncRNAs are localized in the nucleus, where they can participate in chromatin regulation,
transcription regulation, or the formation of nuclear condensates. Cis-acting and trans-acting lncRNAs can
affect interactions with DNA to change chromatin status, both interacting with proteins as transcription
factors or chromatin modifiers, as well as forming direct interactions with chromatin, as triplexes or
R-loops . Some lncRNAs are able to act locally, silencing genes from the chromosome from which they are
[15]
transcribed. The most well-known example of this function is Xist, which has a vital function in X
[22]
chromosome inactivation during female development . This lncRNA is transcribed from the X
chromosome that has to be inactivated. It acts as a guide for several repressive complexes that bind to the
chromatin of the X chromosome, inhibiting the action of RNAPII in the transcription of genes located in
[23]
the X chromosome . lncRNA Kcnq1ot1 also generates repressive environments interacting with chromatin
and targets repressive histone modifiers in order to silence specific genes [24,25] . Unlike the previous case, it
has been reported that some lncRNAs are able to regulate numerous genes throughout the genome. This is
the case of the lincRNA p21, which is regulated by p53 and is capable of repressing the transcription of
multiple genes in trans [Figure 1A]. Other lncRNAs can bind to regulatory factors, such as chromatin
[26]
modification complexes or transcription factors, and act as indirect transcriptional repressors or
[2]
decoys [25,27] , preventing these regulatory factors from binding their target genes . An additional group of
[28]
lncRNAs have been demonstrated to possess the capacity to work as enhancer elements [Figure 1A]. They
are usually classified as enhancer-RNAs (eRNAs) and enhancer-associated lncRNAs (elncRNAs), and they
are able to promote target gene expression by interacting with scaffold proteins or establishing contacts
between enhancers and promoters located far from the genes of interest .
[15]
Interaction between lncRNAs and splicing factors has been described to be essential for the splicing of
different mRNAs, while RNA-RNA duplex formation of some lncRNAs also shows regulation in splicing
[Figure 1B] [15,29] . Additionally, lncRNAs can also act as physical platforms to enable the assembly of dynamic
nuclear structures. For example, lncRNAs such as NEAT1, MALAT1, or PNCTR [15,30] participate in the
recruitment of proteins to form complexes such as paraspeckles, nuclear paraspeckles or perinucleolar
[31]
compartments [Figure 1C] .
The above-mentioned functions occur in the nucleus, but lncRNAs can also perform their roles in the
[32]
[2]
cytoplasm , as they may share processing and export pathways with mRNAs . In this compartment,
lncRNAs are able to regulate several RNA processes, typically by interacting with mRNA molecules.
[33]
lncRNAs can stabilize mRNAs by masking the open reading frame (ORF) [Figure 1D] or sequester
miRNAs due to the presence of complementary sites. This results in a reduced binding of the miRNAs to