Abstract
Long non-coding RNAs (lncRNAs) are a category of non-coding RNAs (ncRNAs) that are more than 200 bases long and play major regulatory roles in a wide range of biologic processes, including hematopoeisis and metabolism. Metabolism in cells is an immensely complex process that involves the interconnection and unification of numerous signaling pathways. A growing body of affirmation marks that lncRNAs do participate in metabolism, both directly and indirectly, via metabolic regulation of enzymes and signaling pathways, respectively. The complexities are disclosed by the latest studies demonstrating how lncRNAs could indeed alter tissue-specific metabolism. We have entered a new realm for discovery that is both intimidating and intriguing. Understanding the different functions of lncRNAs in various cellular pathways aids in the advancement of predictive and therapeutic capabilities for a wide variety of myelodysplastic and metabolic disorders. This review has tried to give an overview of the different ncRNAs and their effects on hematopoiesis and metabolism. We have focused on the pathway of action of several lncRNAs and have also delved into their prognostic value. Their use as biomarkers and possible therapeutic targets has also been discussed.
SIGNIFICANCE STATEMENT This review has tried to give an overview of the different ncRNAs and their effects on hematopoiesis and metabolism. The pathway of action of several lncRNAs and their prognostic value was discussed. Their use as biomarkers and possible therapeutic targets has also been elaborated.
1. Introduction
The long non-coding RNAs (lncRNAs) are classified into mutually nonexclusive subclasses based on their genomic location from where they are transcribed. They can be stand-alone transcripts (also referred to as large intergenic or intervening non-coding RNAs) (Zhang et al., 2019) that typically rarely overlap protein-coding genes (Boland, 2017). LncRNAs can also be transcribed from enhancers, promoters, or intronic regions of other genes (Losko et al., 2016). Bidirectional lncRNA transcripts from the same promoter of a protein-coding gene, but transcribed in the opposite direction. LncRNA transcripts from pseudogenes are natural antisense transcripts (NATs) that can be terminal, nested, or divergent NATs or sense-overlapping lncRNAs that overlap with exon(s) and/or intron(s) of a protein-coding gene in the direction of the sense RNA strand (Dahariya et al., 2019).
The classification of ncRNAs including lncRNAs is not well established because they have many challenges, such as that the nucleotide sequence composition and length of ncRNAs and their transcriptional and post-transcriptional behavior are way too similar to protein-coding RNAs. Currently, there are no precise approaches, and most of them rely on genome annotation for the species. Also, unguided transcripts assembly tools generate truncated partial-length protein-coding transcripts. Thus, they remain as a loosely classified group of RNA transcripts until the present day. For study purposes, lncRNAs are simply classified in terms of structure (linear or circular), action, and location. Linear lncRNAs consist of long intergenic non-coding RNAs (lincRNAs), Transcribed-Ultra Conserved Regions, Enhancer RNA, NAT, etc.; whereas, circular include exonic circular RNA and Exon-Intron CircRNA. Based on the mode of action they could be classified as cis-acting RNA, competing endogenous RNA (CeRNA), or Transacting RNA, and based on location: Intergenic, bidirectional, sense, antisense, or intronic (Bhat et al., 2020).
Like protein-coding mRNAs, lncRNA transcription or biogenesis is also mediated by RNA polymerase II enzymes, and many lncRNAs are structurally similar to mature mRNAs with the absence of introns after the splicing process and the presence of post-transcriptional modifications such as 5′-end methyl-guanosine cap and 3′ polyadenylated tail. However, a set of novel nonpolyadenylated lncRNA transcripts were also discovered recently in various species, and biologists even classify the lncRNAs into polyadenylated or nonpolyadenylated transcripts. Yet, differences and individuality dominate over similarities between mRNAs and lncRNAs, like the absence of a long open reading frame or having a small open reading frame in lncRNAs. mRNAs are longer than lncRNAs because they have a higher number of exons, and the exons in lncRNAs are longer than those in mRNAs. LncRNAs are also transcribed by other polymerase enzymes like RNA polymerase III, IV, or V, besides RNA polymerase II. LncRNAs lack restrain over primary sequence conservation, and they are expressed at relatively lower levels (exceptionally high in lincRNAs). They exhibit more specific expression profiles than mRNAs, but their stability is variable, which is globally lower than mRNAs (Derrien et al., 2012). Splicing is less efficient in lncRNAs, and like macrolncRNAs, vlincRNAs do not even undergo the splicing process. Unlike mRNAs, the subcellular localization of lncRNAs is not restricted to the nucleus, but also to the cytosol and mitochondria. The functional differences between the mRNAs and lncRNAs are prominent enough to be noted (Jarroux et al., 2017).
1.1. Hematopoeisis, Metabolism, and LncRNAs
Hematopoiesis is a process of the formation, development, and differentiation of blood cellular components from hematopoietic stem cells (HSCs). During the hematopoiesis, the self-renewing multipotent long term-HSCs first differentiate into short term-HSCs and then into lineage-restricted hematopoietic progenitor cells, such as common myeloid progenitor and common lymphoid progenitor, and finally, they give rise to all blood cell types. T lymphocytes, B lymphocytes, and natural killer cells arise from lymphoid lineage, whereas megakaryocytes, erythrocytes, granulocytes, mast cells, and macrophages arise from the myeloid lineage (Kondo, 2010; Cavazzana-Calvo et al., 2011). Recent studies have revealed that abnormal hematopoiesis critically contributes to myelodysplastic syndromes (MDS) (Zhang et al., 2019). MDS is a category of clonal myeloid neoplasms marked by aberrant blood cell shape and risk of clonal development to acute myeloid leukemia. LncRNAs are known to be critical for sustaining the hematopoietic stem cell and its lineage diversification into the generation of various blood cells. There is currently limited research that focuses the role of lncRNAs in transcriptional and post-transcriptional modulation all through aberrant Yet, differences and individuality dominate hematopoiesis.
The cell's metabolism refers to all of the biochemical processes that take place inside the cell. Hundreds of biochemical mechanisms occur regularly in cells to keep them alive and functioning. These processes are frequently connected in networks. Energy and dietary transformations, biosynthesis, breakdowns, and by-product expulsion are all metabolic processes that are entirely virtually catalyzed by enzymes. As compared with normal cells, cancer cells have unique metabolic properties that aid proliferation as well as their spread.
LncRNAs are now generally recognized for their vast regulatory impact on a number of metabolic processes in a variety of ways in both normal and malignant metabolism of cells. In this review, we put in a nutshell the advancing field of lncRNAs in hematopoiesis and metabolism and outline the interrelation between the dysregulation of lncRNAs and in myelodysplastic syndromes and tumor metabolism, with a distinct emphasis on particular functions of lncRNAs in glucose, glutamine, and lipid metabolism.
2. LncRNAs Reported in Hematopoiesis
LncRNAs may contain several domains that bind to proteins (transcription factors) or nucleic acid sequences of various genes. The functions of lncRNAs are still an ongoing research area, and their significance is noticed in several biologic processes of both vertebrates and invertebrates. Their role has also been investigated in the area of hematopoiesis. Recent studies suggest that lncRNAs are highly sophisticated regulators of the cell maintenance and differentiation of HSCs. Some of those lncRNAs are involved in hematopoiesis and determined through loss-of-function studies, as explained further in the upcoming sections (Table 1).
2.1. H19
H19 is the first eukaryotic lncRNA discovered. It is a spliced RNA polymerase II transcript with 5′ and 3′ ends and a small open reading frame and is about 2300 nucleotides long. It is highly expressed in long term-HSCs, and its expression is gradually downregulated as long term-HSCs differentiate into short term-HSCs and hematopoietic progenitor cells. H19 lncRNA is also termed as H19 imprinted maternally expressed transcript because its expression depends on the sex of the transmitting parent (maternal), whereas the neighboring IGF2 gene is expressed paternally. This reciprocal expression of H19 and Igf2 is determined by the differentially methylated region (H19-DMR) upstream to the H19 (Gabory et al., 2006). At the same time H19 exon 1 acts as the template for two microRNAs (miRNA), miR-675-5p and miR-675-3p, where miR-675 restricts the expression of Igf1 receptor. The maternal-specific deletion of this control region resulted in activation of the Igf2-Igfr1 pathway and corresponding inactivation of Foxo3-mediated cell-cycle arrest, which leads to upregulated activity and proliferation. Thus, H19 actually promotes HSC quiescence by regulating the Igf signaling pathway (Rajeshkumar et al., 2015). Knockdown experiments revealed another HSC specific lncRNA (lncHSC) that mediates the binding of transcription factors to active promoters of genes encoding hematopoiesis. LncHSC-1 modulates myeloid differentiation, whereas lncHSC-2 modulates in HSC self-renewal and lymphoid differentiation.
2.2. LincRNA-Erythroid Prosurvival
Certain other lncRNAs like lincRNA EC are highly tissue-specific, and they are lost in between the developmental stages from fetus to adult. For example, lincRNAs EC-2, lincRNAs EC-4, and lincRNAs EC-9 are essentially required for fetal erythrocyte maturation, but are absent in the adult bone marrow (Alvarez-Dominguez et al., 2017). A group of lncRNAs such as lincRNA-erythroid prosurvival, enhancer-derived lncRNA, shlncRNA-EC6, and nuclear-localized antisense lncRNA (alncRNA)-EC7 is involved in the megakaryocyte-erythroid progenitor cell into erythrocytes and its subsequent maturation. LincRNA-erythroid prosurvival is a type of lncRNA that facilitates erythrocyte formation by repressing transcription of caspase-activating adaptor proteins from a proapoptotic gene called PYCARD. This repression that protects erythroid progenitors from apoptosis is mediated by chromatin modifiers associated with lincRNA-erythroid prosurvival (Poliseno et al., 2010). From sequence analysis, this lncRNA is found to be 2531 nucleotides long with 4 exons and 3 introns and 5′- 3′ rapid amplification of cDNA. A study implied that this lncRNA is a RNA polymerase III transcript and is highly expressed during the terminal erythroid differentiation.
2.3. Bloodlinc
An enhancer-derived lncRNA named elncRNA-EC 3 was found to be cis-regulating the kinesin family member 2A expressed during the erythrocyte formation. The kinesin family member 2A is a plus end-directed kinesin motor required for assembling normal bipolar spindles, chromosomal movements, and cytoskeletal reorganization, and thus aids in mitosis progression during erythropoiesis (Amelio et al., 2014).
Similarly, the nuclear-localized antisense lncRNA-EC7 (alncRNA-EC7), or Bloodlinc, is a lncRNA that is transcribed from a conserved superenhancer and is about 3700 nucleotides long, capped, and poly-adenylated lncRNA. It enhances the expression of neighboring BAND3 or the anion exchanger 1 coding gene, which belongs to the Solute Carrier 4 family of bicarbonate transporters (SLC4A1). This primary anion exchanger was found to be a predominant glycoprotein of erythrocyte membranes and modulates erythroid maturation (Xu and Shi, 2019). AlncRNA-EC7 accesses its target genes through chromatin interactions stabilized by a nuclear matrix protein called heterogeneous nuclear ribonucleoprotein U (Bensaad et al., 2006). Meanwhile, a knockdown study in mice revealed that small RNA hosts lncRNA [shlncRNA-EC6 (also known as DLEU2)] involved in downregulation of Rac1 and its downstream targets PIP5K, and subsequently results in the activation of enucleation and maturation of erythrocytes (Wang et al., 2018).
2.4. Long Non-Coding Monocytic RNA
High expression of hematopoiesis-specific transcription factor PU.1 in GMPs antagonizes the transcription factor CCAAT/enhancer binding protein (C/EBP)β function and favors monocyte development. In contrast, downregulation of PU.1 results in GMPs' commitment to granulocyte differentiation. This transcription factor regulates the expression of long non-coding monocytic RNA (lnc-MC), and for the same reason, lnc-MC is upregulated during monocytopoiesis (Chen et al., 2015). PU.1 also blocks the silencing of the lncRNA by repressing the expression of miR-199a-5p. Coming to the role of the lnc-MC, its upregulation results in the expression of activin a receptor type 1B, and activin signaling is critical for differentiation of monocyte to macrophage, cytokine production, and cell migration (Ahmad et al., 2020).
2.5. Fas-Antisense 1
Fas-antisense 1 (Fas-AS1) is the first lncRNA to be induced and regulated by erythroid transcription factors during the maturation of erythrocytes. It is transcribed antisense to the intron 1 of the Fas gene. The expression of Fas-AS1 results in decreased expression of Fas on the surface and protects the maturing erythroblasts from Fas-mediated assembly of death-inducing signaling complex and subsequent caspase activation and apoptosis. Fas-AS1 is highly expressed during erythroid differentiation by the activity of erythroid transcription factors, GATA-1 and KLF1, and, in contrast, nuclear factor kappa B (NF-κB) activity decreased the expression of the same (Villamizar et al., 2016).
2.6. LncEry
Recently, a deep sequencing study in murine hematopoietic cell populations revealed the presence of a novel lncRNA and its isoforms. Knockdown and knockout assays were used to confirm its importance in erythroid progenitor differentiation. Since it is highly expressed in erythrocytes and their progenitors it is named lncEry. The downregulation of this lncRNA leads to impaired erythrocyte homeostasis or decreased erythroid differentiation-related genes, including globin genes. LncEry interacts with WD Repeat Domain 82 (Wdr82), a component of the SET Domain Containing 1A, Histone Lysine Methyltransferase (Set1A), and Histone H3-Lys4 methyltransferase. It stabilizes the localization of Set1A/Wdr82 complex to facilitate the epigenetic modification of the promoter region of globin genes, and thereby activating the expression of globin genes by regulating the late-stage of erythropoiesis (Yang et al., 2020).
2.7. LncRNA Eosinophil Granule Ontogeny
During the development of eosinophil from common myeloid progenitor, besides the transcription of proinflammatory molecules and transcription factors (GATA-1, PU.1, c/EBPα, and ϵ), the expression of lncRNA EGO (eosinophil granule ontogeny) was also detected. The isoforms of this RNA transcript have varying lengths; for example, EGO-A is about 1000 nucleotides long, whereas EGO-B is 1700 nucleotides long. EGO is polyadenylated transcript nested within the conserved intron of inositol triphosphate receptor type 1 gene (Aoki et al., 2010). EGO transiently increases interleukin-5 stimulation of high proliferative capacity CD34+ hematopoietic progenitors and facilitates corresponding differentiation into eosinophils. EGO also facilitates expression of an eosinophil granule protein called major basic protein and an antimicrobial protein, known as eosinophil derived neurotoxin (Wagner et al., 2007).
2.8. Lnc-Dendritic Cell
LncRNA dendritic cell (DC) is essential for DC differentiation from DC progenitors, where it activates the signal transducer and activator of transcription 3 (STAT3) by sequestering it away from inhibitory phosphatase, namely SHP1. This favors STAT3 phosphorylation at tyr705, thereby activating dendritic maturation genes. During the myeloid DC progenitor differentiation process, the transcription of lncRNA-DC was upregulated by the electron transport system (ETS)-domain transcription factor PU.1.
2.9. Thy-ncR1
Expression profiling of ncRNAs in T-cell leukemia cell lines revealed the presence of thymus-specific HIT14168 ncRNA known as Thy-ncR1. This lncRNA is transcribed from human chromosome 1 within the olfactory receptor genes. Since the olfactory receptor gene is expressed only in the olfactory bulb and Thy-ncR1 is expressed in organ specific manner, thy-ncR1 may not regulate the olfactory receptor genes expression. However, the expression of the CD1 gene cluster (classic cell surface marker antigen) of nearby locus is highly correlated with Thy-ncR1 expression in the T-cell lineage. Even though CD1 cluster is expressed in both DC and T- cells, Thy-ncR1 does not regulate this gene cluster expression in the DC-cell lineage. Thy-ncR1 also reduces the mRNA microfibril associated protein 4 level in T-cells, thereby modulating the proliferation and differentiation of T-lymphocytes. Normally, microfibril associated protein 4 produces a microfibril associated protein involved in cell adhesion or intercellular interactions, but the physiologic role of this mRNA in immature T cells remains unclear (Aoki et al., 2010).
2.10. Myeloid RNA Regulator of Bim-Induced Death
The p50-Associated cyclooxygenase 2 Extragenic RNA is a type of lncRNA that activates human cyclooxygenase 2 gene expression by sequestering repressive p50 subunits of NF-κB1 away from the Cox2 promoter and recruiting histone acetyltransferase and RNA polymerase II preinitiation complex to enhance histone acetylation (Krawczyk and Emerson, 2014). A novel lncRNA, myeloid RNA regulator of Bim-induced death, termed Morrbid, was recently identified that mediates the survival of human myeloid cells along with neutrophils, eosinophils, and monocytes in response to cytokines by Polycomb repressive complex 2 (PRC2) dependent repression of the proapoptotic Bim transcription. The myeloid RNA regulator of Bim-induced death aids in promoting catalytic activity of PRC2 in the methylation of histone H3 at Lys27 (H3K27me3), thereby leaving the Bcl2L11 gene in poised state (Kotzin et al., 2016).
3. Differential Expression of LncRNAs in MDS
Recent advances in the field of lncRNA-chromatin interactions studies suggest that they might play a role in regulation not only in the normal hematopoiesis, but also in the neoplastic hematopoiesis (Alvarez-Dominguez et al., 2014). These lncRNAs are differentially expressed in both normal and pathologic conditions of hematopoiesis (Gao et al., 2020). The following are the lncRNAs that are known in blood cancers that are either tumor-suppressive or oncogenic (Table 2).
3.1. X-Inactive Specific Transcript
X-inactive specific transcript (Xist), a lncRNA localized on one of the two female X chromosomes in mammals, triggers X chromosome inactivation in the early embryogenesis through transcriptional silencing of one X chromosome to balance gene expression between the sexes. This silencing takes place until embryonic days 4.5–5.5 and the inactive X chromosome enters into a “maintenance phase,” where it propagates as inactive in subsequent cell divisions and Xist is continuously expressed for the reminder of the female life. X chromosome associated cancer in males is also seen but more frequent in trisomy (XXY). The deletion of the Xist gene in female mice revealed that the lncRNA transcript of this gene is essential for hematopoietic stem cell survival and function because heterozygous or homozygous mutants developed a group of blood cancers called myeloproliferative neoplasm and MDS due to progressive reactivation of the inactive X chromosome (Yildirim et al., 2013).
3.2. Homeobox genes (HOX) Antisense Intergenic RNA Myeloid
Homeobox genes (HOX) antisense intergenic RNA myeloid (HOTAIRM), a lncRNA, or more specifically a lincRNA having a genomic location in HOX gene cluster (HOXA, HOXB, HOXC, and HOXD), regulates the expression of several HOX genes. The target of these genes is transcription factors that aid in the transcriptional activation of genes involved in hematopoiesis (Bhatlekar et al., 2018). For example, HOXA9, -B4, and -B6 regulate HSCs' self-renewal, HOX-A5 and -A9 are involved in HSCs' proliferation and differentiation to common myeloid progenitor, and HOXA7 is involved in megakaryocyte differentiation. HOXA9 regulates HSC differentiation into common lymphoid progenitor, HOXB3 regulates differentiation of pre-B lymphocytes into B lymphocytes, and HOXA5 and -C8 regulate differentiation of megakaryocyte-erythroid progenitor cells into erythrocytes; whereas, HOXC3 and -C4 play an important role in the erythroid lineage differentiation and HOXC8 involved in GMP differentiation. HOTAIRM1 is an intergenic antisense lncRNA transcribed between the human HOXA1 and A2 genes specifically in the myeloid lineage, and it is upregulated during granulocyte differentiation. HOX lincRNAs are sometimes found to be overexpressed (from hundreds to nearly 2000-fold) in patients with cancers or tumors (Bhatlekar et al., 2018). For example, overexpression of HOTAIRM1 results in an exaggerated expression of HOXA4 gene and defective differentiation of myeloid progenitor cells. At the same time, the downregulation of HOTAIRM1 in NB4 cell line resulted in decreased granulocytic maturation (Bhat et al., 2020).
3.3. Leukemia-Induced Non-Coding Activator RNA 1
The dysregulation of leukemia-induced non-coding activator RNA 1 expression promotes T-cell acute lymphoblastic leukemia in humans. The leukemia-induced non-coding activator RNA 1 gene is located close to the insulin-like growth factor1 receptor (IGF1R) gene. Upon activation of the neurogenic locus notch homolog protein (NOTCH)-regulated oncogenic ceRNA, the transcription coactivators called mediator complex are recruited on the IGF1R promoter, which interacts with transcription factors and RNA polymerase II, thereby promoting IGF1R expression and IGF1R signaling to induce T-cell acute lymphoblastic leukemia cell proliferation (Trimarchi et al., 2014).
3.4. LncRNA Colorectal Neoplasia Differentially Expressed
Studies in U937 cells and normal mononuclear cells revealed the presence of highly expressed oncogenic lncRNA Colorectal Neoplasia Differentially Expressed in the bone marrow tissues of patients with acute myeloid leukemia (AML) (Wang et al., 2018). LncRNA Colorectal Neoplasia Differentially Expressed promoted the proliferation and inhibited apoptosis in the abnormal myeloid cell line by targeting various miRNAs, genes, and cell signaling pathways, including, for example, Wnt/β-catenin, PI3K/AKT/mechanistic target of rapamycin (mTOR), NF-κB/AKT, mitogen-activated protein kinase, Notch1 pathway, and numerous microRNAs including miR-181a-5p, 136-5p, 217, 384, 203, 186, 205, 145, and 451 (Lu et al., 2020).
3.5. Runt-related transcription factor 1 (RUNX1) Overlapping RNA
Runt-related transcription factor 1 (RUNX1) or AML1, a hematopoietic master regulator that transcribes a Runt-related transcription factor, plays an important role in hematopoiesis. It is considered to be one of the most mutated genes in patients with AML. RUNX1 is required for the production of HSCs, self-renewal or maintenance of HSCs, and the differentiation of diverse hematopoietic cell lineages. The RNA-guided chromatin conformation capture study revealed the presence of a novel lncRNA transcribed upstream of exon 1 and overlapping the protein-coding region of this gene referred to as RUNX1 overlapping RNA. This intragenic lncRNA is about 2160 nucleotides long and directly binds to promoter and enhancer elements of RUNX1 gene. It recruits H3-K27 methylase enhancer of zeste 2, a component of PRC2 to RUNX1, and thereby epigenetically regulates the RUNX1 gene to impair the hematopoiesis.
3.6. MIR99AHG and MIR100HG
LincRNAs MIR99AHG (also known as MONC) and MIR100HG are predominantly expressed in normal hematopoietic stem and progenitor cells (HSPCs) and erythroid cells or megakaryocytic cells. Enforced MIR99AHG expression in normal HSPCs leads to interference in erythroid lineage commitment and development of immature erythroid progenitor cells. MONC and MIR100HG, with their respective miRNA polycistrons, are highly expressed in acute megakaryoblastic leukemia (AMKL) blasts. The knockdown of MIR100HG resulted in a change in lineage surface marker expression, impaired cell viability, and replicating-efficiency of AMKL cells, whereas knockdown of MIR99AHG impaired cell proliferation in AMKL cells (Emmrich et al., 2014).
3.7. Nuclear Paraspeckle Assembly Transcript 1
Nuclear paraspeckle assembly transcript 1 (NEAT1) with two isoforms (NEAT1-1 and NEAT1-2) were recently identified as a crucial component of paraspeckle, a ribonucleoprotein body within the mammalian nuclei. This subnuclear structure with the nuclear-restricted lncRNA regulates the expression of certain genes by nuclear retention of mRNA. Experimental studies revealed the significant downregulation of these NEAT1 isoforms in peripheral blood mononuclear cells of the patient with acute promyelocytic leukemia due to the expression of PML-RARα fusion gene. PML-RARα oncoprotein is an initiation factor for acute promyelocytic leukemia (a subtype of AML) that represses retinoic acid as well as nonretinoic acid target genes transcription and subsequent blockade in promyelocyte (immature white blood cells) differentiation and promotes immature cells' survival. The repression of NEAT1 induced by PML-RARα fusion protein could be reversed by the treatment of all-trans retinoic acid. The increased NEAT1 expression and subsequent decrease in the concentration of leukemic blast cells after all-trans retinoic acid treatment suggests the involvement of NEAT1 lncRNA in cell differentiation and leukemogenesis, but the underlying molecular mechanisms are still unknown (Zeng et al., 2014).
Besides the above mentioned lncRNAs, many more are discovered or suspected to be functional in hematopoiesis in different organisms. However, not all lncRNAs functions, mode of action, and characterization are fully understood, and they are yet to be clinically studied.
4. LncRNA in Normal and Malignant Metabolism
Crosstalk between lncRNAs and cellular metabolism has been implicated in both normal cells and tumor cells. Cancer cells have unique metabolic properties that aid their development and progression when equated to normal cells. These reprogrammed functions, regarded as hallmarks of cancer, are triggered by remarkable alterations in the expression of associated lncRNAs in the specific pathways activated by tumor cells. To showcase the possibilities for targeted therapies in specific cancers, a proposed framework is required to understand the correlation between metabolic reprogramming and lncRNA dysregulation, with a focus on the assigned roles of lncRNAs in carbohydrate, aminoacid, and lipid metabolism in both normal as well as tumor cells (Emmrich et al., 2014).
4.1. LncRNA and Glucose Metabolism
Glucose is the most common final source that reaches tissue and converts to ATP at the cellular level through metabolic transformation. Glucose is essential for energy metabolism. Carbohydrates, lipids, and proteins are all metabolized into glucose or its byproducts in the end. It also stands as an important substrate for various carbohydrates, such as glycolipids, glycoproteins, ribose, and deoxyribose. LncRNAs mediate precise aspects of glucose metabolism varying from regulation of insulin biogenesis in the pancreas, synthesis and breakdown of glycogen, as well as glucose in the liver to maintain homeostasis in various tissues (Shankaraiah et al., 2018).
A lncRNA produced by the β-cell long intergenic non-coding RNA 1 locus has been reported to affect the genesis and activity of islet β cells. Linc1 deletion in mice resulted in glucose intolerance due to abnormal β-cell maturation and secretions. Let-7 together with Akt pathway modulation by lncRNA H19 was found to control pancreatic β-cell growth. In infants, H19 silencing reduced β-cell growth, but re-expression enhanced β-cell expansion in adolescents (Losko et al., 2016).
In pancreatic cells, lncRNA maternally expressed gene 3 (MEG3) has been said to epigenetically control β-cells by regulating the expression of transcription factors such as Rad21, Smc3, and Sin3 via enhancer of zeste 2-mediated methylation (Wang et al., 2018). MEG3 also affects insulin secretion by lowering Pdx-1 and MafA levels (Zhu et al., 2016). Hepatocytes in the liver are accountable in the regulation of major glucose metabolism, such as glycogen production, glycogen breakdown, glucose release into the bloodstream via glycogenolysis, and gluconeogenesis. Many of these processes are under the regulation of various lncRNAs (Bensaad and Vousden, 2007). LncRNA liver glucokinase (GCK) repressor triggered by fasting resembles fasting repressed GCK expression. When lncRNA liver GCK repressor was overexpressed, it lowered the hepatic glycogen level in mice through interaction with nuclear ribonucleoprotein L, a silencer of GCK. LncRNAs have recently been shown to affect glucose metabolism in skeletal muscles. In C2C12 skeletal cells, knocking down the lncRNA-downregulated in hepatocellular carcinoma lowered glucose production and elevated glucose transporter expression (Lu et al., 2020).
Metabolic reprogramming of glucose is common in a variety of clinical conditions, especially in cancer. The Warburg effect, for instance, is the preferentially important example among them. LncRNAs have a myriad of repercussions in glucose metabolism in pathologic conditions. They are a part of the development of biologic processes in cancer, mediated through the regulation of various receptors, enzymes, transcriptional factors, and signaling molecules. The silencing of lncRNA antisense non-coding RNA at the INK4 locus (ANRIL) reduced glucose absorption and hindered acute myeloid lukemia development by targeting adiponectin receptors at the cellular level (Qin et al., 2016).
4.1.1. LncRNA Mediated Regulation of Metabolic Enzymes and Transcriptional Factors
LncRNAs control energy metabolism substantially by modifying metabolic enzymes and transcription factors involved in metabolism after they have been translated (Fig. 1). The link between lncRNAs and metabolic enzymes is very intricate due to their significant effect on each other. LncRNA-mediated post-translational changes adversely impact metabolic enzymes, such as HK (hexokinase) and pyruvate kinase to alter glucose metabolism in different malignancies, such as cancers (Sun et al., 2018). The initial and irreversible stage of glycolysis is catalyzed by HK. In osteosarcoma, upregulation of the lncRNA plasmacytoma variant translocation 1 amplified glucose metabolism via modulating the miR-497/HK2 axis. The rate-limiting enzyme in glycolysis is pyruvate kinase, whose mode of action is influenced through both allosteric and covalent changes. Pyruvate kinase M2 (PKM2) produces ATP by catalyzing the conversion of phosphoenolpyruvate to pyruvate. By inhibiting aerobic glycolysis by means of the AKT/mTOR signaling pathway, the lncRNA LINC01554 facilitated ubiquitin-mediated degradation of PKM2 in hepatocellular carcinoma (Zheng et al., 2019). Additionally, the lncRNA highly upregulated in liver cancer (HULC) boosted phosphorylation of lactate dehydrogenase A (LDHA) and PKM2, which improved glycolysis and promoted the proliferation of liver cancer cells (Shankaraiah et al., 2018). LncRNA actin gamma 1 pseudogene (AGPG) influences the expression of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 2, which is important in glucose metabolism through its phosphorylation activity (Wang et al., 2018). Others on the list include lncRNAs such as LINC00092, XIST, and urothelial carcinoma associated 1 (UCA1), which have been discovered to affect glucose metabolism through altering the same enzyme (Sun et al., 2018).
Since lncRNA alters the control of transcription factors on their targets, they can amend energy metabolism via modulating metabolism-associated transcription factors. LncRNAs control the function of these polypeptides by different post-translational modifications, including phosphorylation and ubiquitination of the target transcription factors and boosting the expression of enzymes involved in metabolism.
LncRNA Rhabdomyosarcoma 2-associated transcript is needed for neuronal development because it promotes SOX2 binding to nearly 50% of its binding sites. LncRNAs appear to have an essential role in controlling hypoxia-inducible factor 1 (HIF-1) activity. In several metabolic disorders, lncRNA suppressed HIF-1 hydroxylation and breakdown and favored aerobic glycolysis by preventing the connection between prolyl hydroxylase domain protein 2 (PHD2) and HIF-1. Another lncRNA, cancer susceptibility 9, interacts with HIF-1, leading to induction of HIF-1, thereby stimulating glycolytic metabolism in reprogramed cells (Sun et al., 2018). Knocking down the lncRNA UCA1 increased the cytotoxic potential of adriamycin and impeded HIF-a-dependent glycolysis, which has been shown to help patients with acute myeloid leukemia to overcome chemoresistance (Zhang et al., 2018).
Furthermore, the post-translational alteration of c-Myc by lncRNAs has been linked to the jurisdiction of cancer energy metabolism. The glycolysis-associated lncRNA of colorectal cancer safeguards c-Myc against ubiquitination by associating specifically with the heat shock protein 90 (Yuan et al., 2019). Interestingly, the transcriptional profile change of c-Myc target genes like LDHA lead to reprogramming glycolytic metabolism for colorectal cancer (CRC) cell growth. Additionally, in multiple myeloma, the lncRNA PD1A3P associates with c-Myc to improve its transactivation and boosts pentose phosphate pathway by interacting with the promoter of glucose 6-phosphate dehydrogenase (Zhang et al., 2018). Increased ubiquitination of c-Myc and its target genes implicated in the glycolytic process, such as LDHA and HK2, have been linked to lncRNA MEG3 overexpression (Xu and Shi, 2019). Several lncRNAs have indeed been correlated to transcription factors in the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) cascade in a variety of ways.
Disruptions in metabolism-related proteins are characterized by significant changes in metabolic signaling networks. The AMP-activated protein kinase (AMPK), AKT, mTOR, and p53 are particularly prominent among the main effector molecules that play a central role in these regulations (Fig. 2).
4.1.2. lncRNA and Central Players of Metabolism
Many studies in recent years have observed alteration of various signaling pathways in relation to lncRNA expression patterns. Nevertheless, just a limited amount of studies explain the regulatory mechanism. Due to their capability to influence multiple factors of signaling cascades, such as AKT, mTOR, P53, and AMPK, lncRNAs have surfaced as potentially therapeutic, and their deregulation plays a significant role in pathology of many human malignancies.
Akt.
The serine/threonine kinase Akt (protein kinase B) is a crucial regulator of cell signaling. Stimulation by growth factors leads to activation of Akt, resulting in phosphorylation and inhibition of multiple elements of the apoptotic pathway and preventing cell death. Akt genes have distinct functions in normal cell physiology and cancer pathogenesis and are expressed both at the mRNA and protein levels. Apoptosis-related kinases and glucose transporters (GLUTs) are two metabolic variables linked to Akt. Akt activation can boost both ATP synthesis and oxygen uptake in cells. Akt controls glycolysis through a variety of ways, including raising GLUT expression and increasing the production of glycolytic enzymes such as HK2 and PKM2 and suppressing mitochondrial respiration.
In many metabolic pathways, Akt is a main server among several signaling cascades, and it is quite often altered by different lncRNAs. Metastasis associated lung adenocarcinoma transcript 1 (MALAT1), LINK-A, LINC00470, and AK023391 are examples of lncRNAs that enhance the activation of the Akt signaling pathway through a variety of methods (Yuan et al., 2019). LINC00470 glues to the FUS protein, trapping Akt in the cytoplasm and boosting its activity. In xenograft malignant cells, the lncRNA AK023391 modulates the expression of Ki-67, p-FOXO3a, p-PI3K, p-AKT, and p-NFkB. Recently, FAL1, an lncRNA that suppresses p21 by deregulating its transcription and stimulates cell proliferation, has been discovered. The lncRNA FER1L4, on the other hand, promotes cell cycle arrest through regulating the Akt signaling pathway. LncRNA H19 works as a molecular sieve to block the action of miRNA let-7. The phosphorylation of the miRNA processing factor k5RP by the PI3K/Akt/pathway lowers H19 expression. H19 inhibition raises let-7 levels, hindering the insulin/PI3K/Akt pathway and resulting in decreased glucose absorption. The Akt signaling pathway is also inactivated by lncRNAs. For example, lncHD1 regulates the sterol regulatory element-binding protein 1 (SREBP-1c) protein level, which is a major regulator of lipid metabolism in many malignancies, via modulating the phosphorylation of the PDK1/Akt/FOXO cascade (Krycer et al., 2010).
mTOR.
mTOR is a significant signaling center that regulates necessary cellular responses and metabolism. mTOR is a PI3K-related serine/threonine-protein kinase that is a catalytic member of two different protein complexes called mTORC1 and mTORC2, which differ in their mode of action as well as in their structure. Gene transcription, translation, endocytosis, and other growth-related activities are all regulated by mTORC1, whereas the function of mTORC2 is unknown. However, it is assumed to enhance cell survival and actin cytoskeleton structure. Although several regulators participate in the regulation of mTOR activity, new research has revealed lncRNAs as putative mTOR controllers.
According to recent reports, UCA1 activates mTOR by overexpressing HK2 and promotes glycolysis by activating STAT3 and blocking miR-143. In bladder cancer cells, this revealed a new cascade of regulation on the metabolism of glucose in UCA1-mTOR-STAT3/miR-143/HK2 axis. LncRNA ANRIL has been shown to aid neural progenitor cell development by upregulation of GLUT1 and LDHA. The mechanism of action likely entails ANRIL-induced Akt phosphorylation, resulting in stimulating the mTOR pathway, which in turn potentiates GLUT1 and LDHA levels, leading to increased neural progenitor cell development (Zou et al., 2016). MetaLnc9, also known as LINC00963, interacts with the phosphoglycerate kinase 1 protein and is found on chromosome 9 (Amelio et al., 2014). This connection stops the phosphoglycerate kinase 1 from being ubiquitinated, resulting in accumulation of phosphoglycerate kinase 1 and mTOR activation. Many lncRNAs in the Dlk1-Gtl2 locus give birth to numerous miRNAs that aim for mTOR components. Dlk1-Gtl2 expression is essential for the maintenance of HSCs in the mouse fetal liver, and ablation of imprinting at the loci results in a large decrease of HSCs, owing to AKT-mTOR overexpression and metabolic problems (Aquilano et al., 2013).
AMPK.
AMP-activated protein kinase (AMPK) is a crucial energy monitor in cells. When AMPK is active, the TSC2 complex is triggered, which leads to the deactivation of the mTOR-stimulated GTP-binding protein RHEB. Impaired AMPK signaling, a crucial metabolic gatekeeper, contributes to high cell division and diminished autophagy in energy-stressed cells. Once intracellular ATP levels have dropped, the tumor suppressor LKB1 acts as an upstream regulator of kinases, phosphorylating and stimulating AMPK. As a result, when AMP is present, ATP-depleting processes are significantly suppressed, and ATP generation is accelerated in the body (Shackelford et al., 2009). LncRNA LINC00473, as well as the neighbor of BRCA1 gene 2 (NBR2), are found to be associated with LKB1 dysregulation. LKB1 inactivation prompted LINC00473, whereas the LKB1-AMPK signaling pathway promoted lncRNA NBR2. By regulating the levels of AMPK kinase, NBR2 can operate as a tumor suppressor (Liu et al., 2016). AMPK slows ATP-drained anabolism and promotes ATP-induced catabolism via promoting a variety of downstream effectors. The NBR2, linc00473, and LKB1/AMPK pathway could therefore play a big part in cancer cells through modulating pathways involved in many cellular metabolisms (Chen et al., 2016).
P53.
Most human cancers effectively inhibit the transcription factor p53, which acts as a tumor suppressor. The lack of p53 in a cell can result in mitochondrial respiratory impairment, as well as an upsurge in glycolysis (Bensaad and Vousden, 2007). P53 suppresses the activity of GLUT1 and GLUT4 while boosting HK, SCO2, and phosphatase and tensin homolog. Several p53-related lncRNAs have been implicated in metabolic diseases (Kim et al., 2016). MALAT1 was discovered to modulate p53 levels, and MALAT1 knockout fibroblasts accelerated DNA damage repair, resulting in p53 activation and consequent target gene expression (Chen et al., 2012). In nasopharyngeal cancer, the HULC lncRNA HULC has been seen to suppress the function of p53 and p21 to encourage cell proliferation.
4.2. LncRNA and Lipid Metabolism
Lipids are fundamental components of membranes, energy stores, and signal molecules, which are essential for cell survival. The liver and adipose tissue are the key systems for generation of energy, as well as storage. Lipid metabolism is a complicated process, since it involves many distinct molecular networks and transcriptional factors, some of which have been studied so far. Many disorders of considerable relevance to human health, such as nonalcoholic fatty liver disease and cardiovascular diseases, are caused by the dysregulation of lipid homeostasis mechanisms. Non-coding RNAs have surfaced as essential integrators of lipid metabolism in both the cell and the body. The link between different lncRNAs associated with lipid metabolism and their modes of action has been demonstrated. The majority of the associated molecular mechanisms are based on lncRNA-RNA or lncRNA-Protein interconnections, where they function either as transcription regulators that function at the DNA level, post-transcription and translation controllers that operate at the RNA level, and lastly as post-translation regulators that work at the protein level.
4.2.1. Role of LncRNA in Lipoprotein and Triglyceride Metabolism
Adipocyte maturation and triacylglycerol synthesis are both influenced by lncRNA Blnc1 via liver X receptor (LXR) stimulation. Overexpression of Blnc1 greatly boosted SREBP1c expression, thereby elevating gene expression involved in the synthesis of triacylglycerol and hepatic steatosis in primary hepatocytes (Bensaad et al., 2006). When LXRs were mechanistically activated through drugs, the expression of lncRNA LeXis elevated in the liver, acting as a moderator of genes implicated in cholesterol homeostasis (Li et al., 2017). In mice, triggered LeXis lowered cholesterol biosynthetic pathway gene expression levels, particularly SREBF2 and 3-hydroxy-3-methylglutaryl-CoA reductase, as well as systemic and hepatocyte total cholesterol. In mouse hepatic cells, palmitate-stimulated enhancement of MALAT1 expression was accompanied by a rise in SREBP1c level in primary murine hepatocytes via its ubiquitination and thereby stabilization of SREBP-1c in the nucleus. Knockdown of MALAT1 reduced MALAT1 to SREBP-1c interaction, resulting in the accumulation of lipid in hepatocytes (Li et al., 2017). In in vivo studies of lncRNA, lncARSR has shown that overexpression of the lncRNA has boosted liver cholesterol biogenesis by upregulating the rate-limiting enzyme, 3-hydroxy-3-methylglutaryl-CoA reductase, in the biogenesis of cholesterol. LncARSR leads to the activation of SREBP-2, a key transcription factor of the rate-limiting enzyme through PI3K/Akt pathway. Also, H19 levels in hepatocytes were found to become higher by diet-induced fatty liver, resulting in increased triacylglycerol buildup (Schmidt et al., 2018). The activity of apolipoproteins that serve as a source for plasma lipoproteins production has been found to be regulated by two AS lncRNAs, APOA1-AS and APOA4-AS. However, the mechanism of action needs to be studied (Qin et al., 2016). LncRNA BM450697 regulates low-density lipoprotein receptors, important for swallowing and eliminating low-density lipoprotein receptor particles from circulation. Low-density lipoprotein receptors are activated by BM450697 silencing. The inhibition of interactions with RNA pol II and perhaps SREBP1a at the low-density lipoprotein receptor promoter by BM450697 resulted in a reduction in low-density lipoprotein receptor mRNA levels. New data suggests that lncRNAs have a role in adipogenesis, promoting lipid storage and disposal. The lncRNA SRA1, for instance, has been shown to induce preadipocyte development in part through linking to peroxisome proliferator-activated receptor (PPAR)v by acting as a ceRNA for miR-31 to target C/EBP-α in adipose tissue-derived mesenchymal stem cells (Nuermaimaiti et al., 2018; Li et al., 2019).
Lipid metabolism may also undergo adaptations in the metabolic reprogramming of tumor cells, which require a high quantity of lipids to create organelles and key signaling components throughout aggressive proliferation and have their lipid biosynthesis altered to a substantial extent. In these cells, lncRNAs may have a role in the control of various fat metabolism-associated genes. For example, in cervical cancer, lncRNA-lymph node metastasis in cervical cancer (LNMICC), by modulating a facilitator of fatty acid absorption and trafficking fatty acid-binding protein 5. enables reprogramming to improve lymph node invasion. Fatty acid synthase N (FASN) is a crucial rate-limiting enzyme of fatty acid synthesis. LncRNA HOTAIR expression is favorably linked with FASN expression in human nasopharyngeal cancer. Knocking down HOTAIR diminished free fatty acid and FASN levels at the genomic level. Other lncRNAs, such as NEAT1, promote uptake of lipids in macrophages through miR-342-3p-CD36 axis. NEAT 1 also has shown to modulate adipose triglyceride lipase (ATGL) expression and impact the aberrant lipidosis of hepatocellular carcinoma cells (Wang et al., 2019). Two lncRNAs, growth arrest-specific transcript 5 and RP5-833A20.1, have been found to reduce the efflux of cholesterol in macrophage derived cells. Growth arrest-specific transcript 5 regulates cholesterol levels through suppression of ATP-binding cassette transporter 1 transcription, whereas RP5-833A20.1 exert their regulation through miR-382-5p-NFIA axis (Dhanoa et al., 2018).
Research has shown that lncRNAs operate on the promoters of the gene associated with lipid metabolism. When mice primary hepatocytes were treated with GW3965, an agonist to the liver X receptor (LXR), which governs cellular cholesterol homeostasis and suppresses cholesterol production, the lncRNA LeXis, was found to be the most upregulated among the other lncNAs. The presence of an LXR response element in the LeXis promoter was later demonstrated utilizing a luciferase reporter experiment (Cheng et al., 2020).
The dysregulation of the lncRNA HULC has been linked to a variety of cellular processes, including hepatoma cell proliferation and infiltration. In hepatoma cells, cholesterol drives HULC production through the retinoic receptor RXRA, which enhances lipogenesis by inhibiting miR-9 target PPARs. HULC suppresses miR-9 expression by methylating the CpG islands, which epigenetically silences the miR-9 promoter. This will lead to higher PPAR expression of the fatty acid synthase and acyl-CoA synthetase. This suggests that it is unreasonable to disregard the importance of lncRNA-mediated metabolic reprogramming in tumor development. They could be used in conjunction with other cancer treatments.
4.3. LncRNA and Amino Acid Metabolism
Amino acids are the building blocks of proteins, a vital macromolecule that is further modified into various essential cellular effectors and regulator components, such as enzymes, hormones, and neurotransmitters. A succession of enzymatic and transcriptional events complete the intracellular metabolism of amino acids (Firmin et al, 2017). LncRNA has been discovered to be engaged in the mechanism of amino acid metabolism by regulating these molecules, in addition to being implicated in the control of glycolysis and lipid metabolism (Fig. 3). Many of them have found different functions, such as modulating enzymes and the glutaminase alternative splicing pathway, as a competing endogenous RNA, which coordinates with glutamine metabolism-associated miRNA. In addition, certain amino acid transporters have been identified to be regulated by lncRNAs, and many control the protective effects against antioxidants in cells. However, more confirmative studies are needed to be performed for identifying their exact mode of action.
A growing body of data suggests that cancer cell growth is aided by a relatively high requirement for amino acids. A range of amino acids serves an increasingly important role in tumor metabolism (Sivanand and Vander Heiden, 2020). Prior investigations have revealed information about the involvement of glutamine in cancer. Cancer cells rely on an external glutamine supply for amino acid metabolism. Glutamine is a key reservoir of reduced nitrogen for various metabolic pathways, as well as a supplier of carbon to refill the tricarboxylic acid cycle. UDP-N-acetylglucosamine is a component in protein folding and trafficking, and glutamine aids in its production. Protein folding will be defective, and the endoplasmic reticulum (ER)-related stress response will be triggered in the absence of glutamine in the cells. Knowledge of how lncRNAs are related to amino acid metabolism, especially glutamine metabolism in malignant cells, is still at the preliminary stage. The hepatocellular carcinoma-associated lncRNA HOXA transcript at the distal tip, which is an oncogene, is implicated in GLS1-associated metabolism of glutamine, and overexpression of HOXA transcript at the distal tip is expected to promote GLS1 expression and hence glutamine metabolism (Ge et al., 2015). By sponging miR-145, lncRNA taurine-upregulated gene 1 has been shown to increase glutamine metabolism in intrahepatic cholangiocarcinoma. Sirt3, a direct target of miR-145, has been shown to favorably regulate glutamate dehydrogenase (GDH) production by deacetylating GDH in the mitochondrial matrix (Zeng et al., 2017). Another lncRNA, prostate cancer gene expression marker 1, has been shown to affect prostate cancer metabolism, especially tricarboxylic acid and glutamine metabolism, by activating c-Myc, which recruits prostate cancer gene expression marker 1 to the promoters among its gene of interest, resulting in increased transactivation activity. LncRNA HOTAIR expression is discovered to be aberrantly elevated in glioma cells. It was found, since the lncRNA HOTAIR acts as a sponge for miR-126-5p and increases glutamine metabolism (Schlicker et al., 2008). Polypeptides synthesized from lncRNA have been proven to prevent cancer in amino acid metabolism in recent data. LncRNA HOXB-AS3, for example, slows down colon metastasis through a conserved peptide comprising 53 residues that suppresses amino acid metabolism. The influence of lncRNAs on glutamine metabolism and other aspects of amino acid metabolism in tumor cells have to be investigated further, since it might lead to effective therapeutic intervention.
4.4. Therapeutic Potential of LncRNA
LncRNAs are involved in almost every biologic activity and have been related to a number of diseases. The mechanisms through which lncRNAs regulate gene expression are poorly understood. RNA-based therapeutic methods have made substantial progress in recent years. The results of the research have recognized several advantages of using lncRNA as therapeutic targets. LncRNAs have grown to become a promising new class of molecules with the potential to alter diagnosis and treatment (Kim, 2020).
There is a well established relationship between lncRNA and disorders, notably malignancies. Several non-coding RNAs have been found as diagnostic and prognostic indicators as a result of the discovery of their functions in cancer (Wang et al., 2020). Recent findings have shown the significance of lncRNAs in a wide variety of clinical conditions other than cancer, such as metabolic disorders (Ema et al., 1990). Because of their significant functions in different aspects of cellular metabolism, they are important. It's a new field with a lot of potential for future lncRNA-mediated therapies focused against various metabolic disorders.
Moreover, diseases, such as immunologic dysfunction, have been linked to lncRNAs in research. According to mounting data, long non-coding RNAs (lncRNAs) are critical regulators of viral diseases and host immune responses, covering mechanisms involved in the control of coronavirus disease (COVID-19) and consequent clinical conditions (Henzinger et al., 2020). Cellular lncRNAs govern genetic material and influence viral replication and pathogenesis during viral infections by influencing the host transcriptome via virus-mediated changes. Certain lncRNAs have important regulatory functions in the viral course of infection in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). MALAT1 and NEAT1 lncRNAs do seem to be strongly linked to immunologic responses and may play a role in the inflammatory course of SARS-CoV-2 infected cells, according to the latest reports (Henzinger et al., 2020; Agwa et al., 2021). Elevated levels of LINC02207 and LINC01127 were known to be correlated to severe COVID-19, whereas LINC02084, LINC02446, LINC00861, LINC01871, and ANKRD44-AS1 were discovered to be correlated to mild COVID-19. When comparing patients with severe COVID-19 to patients with mild COVID-19, plasmacytoma variant translocation 1 was also found to be downregulated. In the clinical treatment of COVID-19, medications such radecivir, baritinib, dexamethasone, and tocilizumab are already being used (Cheng et al., 2021). Focused studies might lead to the development of lncRNA-based techniques and therapeutics by determining the prevalence and role of lncRNAs during SARS-CoV-2 infection. More research is needed due to the numbers of lncRNAs coded by the human genome and the lack of coherence on the altered lncRNA in SARS-CoV-2 infection.
5. Conclusion
The heterogeneity of responses seen in various tissues and disorders exemplifies the varied roles of lncRNAs in the cell. A deeper knowledge of the functions of lncRNAs in various phases of hematopoiesis and metabolism, as well as their altered regulation in hematopoietic and metabolic diseases, would be beneficial in improving disease prediction and would lead to innovative treatment techniques that target regulatory molecules. The studies reviewed here have provided enough evidence that lncRNAs play vital roles in regulating various stages of hematopoiesis. Involvement of more functional studies is required to look at the role of lncRNAs in transcriptional and post-transcriptional modulation throughout hematopoiesis and how its aberrant expression results in the dynamic progression of myelodysplastic syndrome. As previously mentioned, the interaction of lncRNAs with key transcription factors or metabolic enzymes efficiently impacts glucose, lipid, and amino acid metabolism while also promoting tumor growth. Pathways such as PI3K/AKT/mTOR, p53, and AMPK, which are integral for the regulation of glucose metabolism, especially in cancer, are under the regulation of different lncRNAs. They are also shown to have an impact on lipid metabolism, such as apolipoproteins, cholesterol, and triglyceride metabolism via interacting with SREBP transcription factors. Furthermore, lncRNA has been found to play functions in amino acid metabolism, altering amino acid transporters and controlling glutamine metabolism specifically in cancer. Despite the fact that numerous essential biologic roles of lncRNAs have been found in the last years, the vast majority of lncRNAs remain uncharacterized, and there is a good distance to cover before we can define, describe, and interpret the real functions of lncRNAs. As a result, a thorough analysis of the importance of lncRNA in regulating different targets and even the strategies by which it achieves it, would therefore aid in the development of new tools to manage myelodysplastic and metabolic syndrome, as well as the development of improved treatment interventions.
Authorship Contributions
Wrote or contributed to the writing of the manuscript: Sangeeth, Malleswarapu, Mishra, Gutti.
Footnotes
- Received November 12, 2021.
- Accepted May 13, 2022.
This work was supported by University of Hyderabad-Institution of Eminence [Grant No. UOH-IOE-RC3-21-006]; Science and Engineering Research Board [EEQ/2018/00853]; Indian Council of Medical Research [56/5/2019-Nano/BMS]; and DBT BUILDER and Council of Scientific and Industrial Research [No. 27(0343)/19/EMR-II] grants of the Government of India. We appreciate the funding in the form of UGC Fellowships from the Government of India.
No author has an actual or perceived conflict of interest with the contents of this article.
Abbreviations
- alncRNA
- nuclear-localized antisense lncRNA
- AMKL
- acute megakaryoblastic leukemia
- AML
- acute myeloid leukemia
- AMPK
- AMP-activated protein kinase
- ANRIL
- antisense non-coding RNA at the INK4 locus
- C/EBP
- CCAAT/enhancer binding protein
- CeRNA
- competing endogenous RNA
- COVID-19
- coronavirus disease
- DC
- dendritic cell
- EGO
- eosinophil granule ontogeny
- Fas-AS1
- Fas-antisense 1
- FASN
- fatty acid synthase N
- GCK
- glucokinase
- HIF-1
- hypoxia-inducible factor
- HK
- hexokinase
- HOTAIRM
- HOX antisense intergenic RNA myeloid
- HOX
- homeobox genes
- HSC
- hematopoietic stem cell
- HULC
- highly upregulated in liver cancer
- Igf1r
- insulin-like growth factor1 receptor
- LDHA
- lactate dehydrogenase A
- lincRNA
- long intergenic non-coding RNA
- lncHSC
- HSC specific lncRNA
- lnc-MC
- long non-coding monocytic RNA
- lncRNA
- long non-coding RNA
- LXR
- liver X receptor
- MALAT1
- metastasis associated lung adenocarcinoma transcript 1
- MDS
- myelodysplastic syndromes
- MEG3
- maternally expressed gene 3
- miRNA
- microRNA
- mTOR
- mechanistic target of rapamycin
- NAT
- natural antisense transcript
- NBR2
- the neighbor of BRCA1 gene 2
- ncRNA
- non-coding RNA
- NEAT1
- nuclear paraspeckle assembly transcript 1
- NF-κB
- nuclear factor kappa B
- PKM2
- pyruvate kinase M2
- PPAR
- peroxisome proliferator-activated receptor
- PRC2
- Polycomb repressive complex 2
- RUNX1
- runt-related transcription factor 1
- SARS-CoV-2
- severe acute respiratory syndrome coronavirus 2
- SREBP1
- sterol regulatory element-binding protein 1
- STAT3
- signal transducer and activator of transcription 3
- UCA1
- urothelial carcinoma associated 1
- Xist
- X-inactive specific transcript
- Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics