## 3 Global Mechanisms of LncRNA Functions  
It has been shown that lncRNAs can elicit gene activation or suppression by interacting with proteins, DNAs and RNAs including miRNAs [2,3,6,7,8]. LncRNAs can act as molecular scaffolds to affect gene  
Figure 1: Schematic diagram of representative classes of lncRNAs. Long non-coding RNAs are divided into five subgroups. The groups are based on the genomic locations where the lncRNAs are transcribed from the non-coding sequences. expression by interacting with proteins such as transcription factors or components of chromatin modifying complexes (Figure 2A). Other proposed mechanisms of action of lncRNAs include targeting proteins to specific genomic sites such as promoter regions by complementary interactions with DNAs. An alternative scenario is that interactions with DNAs prevent the binding of specific proteins to the DNA regions (Figure 2B). Lastly, lncRNAs can also base pair with other RNA molecules such as mRNAs or may act as endogenous sponges for miRNAs (Figure 2C), which in turn negatively regulates other RNAs' functions [2, 3, 6, 7, 8]. As aforementioned, lncRNAs exhibit several molecular functions such as signaling, decoys, guides, and scaffolds to regulate health and disease [2, 22]. In the last decade, it has been found that lncRNAs participate in molecular signaling by being transcribed at specific spatial and temporal points. It has been also shown that lncRNAs can act as signaling molecules to modulate gene or allele function. For instance, lncRNAs have been shown to involve in X chromosome inactivation [22, 23]. Mammalian organisms are diploid and are born with two alleles per an autosomal gene. In female eggs, two X chromosomes are present but only one allele can be expressed within the egg. Xist, a lncRNA, regulates gene expression by interacting with one of the X chromosomes and inactivating X alleles [23]. This process occurs during female development in which Xist RNA is produced from the inactivated X allele. Xist interacts with the X allele from which it was originally transcribed. The binding of Xist to the inactivated X allele represses the allele's overall capability of gene expression. Xist can be repressed by an antisense lncRNA called Tsix, while it can also be activated by another lncRNA called Jpx [22]. The presence of the transcribed Xist from X allele demonstrates how active genomic silencing occurs through molecular signaling and the negative regulation of lncRNAs [23]. LncRNAs act as negative regulators to down-regulate the functions of targeted proteins [24]. For example, lncRNAs act as molecular decoys and regulate cellular processes by targeting and sequestering specific proteins. An lncRNA named PANDA was revealed to have decoy functions by  
Figure 2: Schematic diagram of lncRNA mechanisms of action. LncRNAs function to regulate gene expression by diverse mechanisms. (**A**) LncRNAs act as molecular guides and scaffolds to interact with protein complexes. LncRNAs also act as molecular decoys for proteins including transcription factors; (**B**) lncRNAs modulate the epigenetics through guiding chromatin-modifying complexes to target genomic DNA loci; (**C**) lncRNAs act as endogenous sponges for other RNAs such as mRNAs and miRNAs. ORF: open reading frame. which it deactivated nuclear transcription factor Y subunit \(\alpha\) (NF-YA), a positive regulator of apoptosis. During low levels of DNA damage in the cell, PANDA becomes activated and is transcribed in a p53-dependent manner. PANDA then directly binds to NF-YA to protect the cells from undergoing apoptosis. It is also shown that knockdown of PANDA in human fetal fibroblasts led to increased levels of NF-YA and cell apoptosis [24]. LncRNAs can also function as molecular guides by directing proteins to specific targets in the cell and determining gene expression in the _cis_ and _trans_ positions [25]. A central platform used as a molecular scaffold is another function of lncRNAs. For instance, lncRNAs are considered as important elements for cellular stabilization [26].