The Roles of Long Noncoding RNA in Depression

Depression is a common psychiatric disorder that brings great pain and burden to patients and their families. However, the pathogenesis underlying the development of depression remains unclear, limiting the development of diagnostic and therapeutic approaches for the disease. Recently, an increasing number of studies have shown that long noncoding RNAs (lncRNAs) play modulatory roles in depression. Here, we summarize the general mechanism of action and their roles in depression. LncRNAs are suggested to exert regulatory functions in depression in various ways, including competing endogenous RNA (ceRNA) networks, interacting with epigenetic modifications, interacting with single-nucleotide polymorphisms (SNPs), acting in cis or trans on target genes and regulating the immune system. A total of 13 lncRNAs (involving 16 ceRNA regulatory axes) have been revealed to have regulatory mechanisms. The potential relationship between methylation modification and lncRNA was also analyzed through lncRNA expression profile data. Functional annotation analysis showed that methylation-related lncRNAs were mainly enriched in postsynaptic specialization, neuron-to-neuron synapses, asymmetric synapses, and postsynaptic density. This indicates that methylation-related lncRNAs may have an impact on the synaptic microenvironment and may thus contribute to the development of depression. Moreover, we predicted potential interactions between SNP sites and lncRNAs in depression by querying the database. Through this review, we hope to deepen the understanding of the regulatory landscape of lncRNAs in depression and propose that future efforts should focus on establishing comprehensive and robust diagnostic models and further revealing the exact mechanism of lncRNA action in depression by experimental evidence


Introduction
Depression is a severe affective mental disorder with typical clinical manifestations of depressed mood, reduced volitional activity, and slowed thinking and may be accompanied by somatic discomforts, such as abdominal distention, chest tightness, and pain [1].More than 300 million people suffer from severe depression, with a lifetime prevalence rate of 17% [2].In 2010, depression accounted for 8.2% (5.9%-10.8%) of global years lived with disability and 2.5% (1.9%-3.2%) of global disability-adjusted life years [3].Depression causes great losses to human health and property.By the end of 2030, depression is expected to impose the world's leading disease burden.This is because individuals with early onset depression are less likely to complete secondary education (2-3 times), and this population has a higher unemployment rate (29% at age 40) than that of the general population [4,5].Although the exact pathogenesis of depression has not been determined, it is generally believed that genetic factors are one of the causes of depression [6,7].Based on different pathogenesis hypotheses, genes related to neurotrophic factors, monoamine neurotransmitters, and neuroendocrine factors have received attention; these genes include BDNF [8], COMT [9], and NET [10].In a large genome-wide association meta-analysis study involving 135,458 cases and 344,901 controls, 44 variants were identified as genetic risk factors for depression.However, these findings are still insufficient to provide us with a comprehensive understanding of the pathogenesis of depression and to find corresponding strategies.
Recent studies have confirmed that in different biological lineages, the protein coding sequence of the genome remains relatively stable, while the noncoding sequence shows a significant correlation with the heterogeneity and complexity of the organism [11,12].Long noncoding RNAs (lncRNAs), which account for 80%-90% of all noncoding RNAs (ncRNAs), are RNAs with a length of more than 200 nucleotides but no protein coding activity [13].Compared with microRNAs (miRNAs), circular RNAs (circRNAs), and other ncRNAs, lncRNAs have long sequences and complex spatial structures and can bind to many diverse proteins.Thus, they carry more information and perform more diverse functions.LncRNAs can act at multiple levels, including the pretranscriptional, posttranscriptional, translational, and posttranslational levels.The primary mechanisms include the following: (1) acting as a "sponge" for miRNA, competitively blocking its binding to target mRNAs; (2) interfering with the expression of genes through cis or trans regulation; (3) participating in epigenetic modifications of DNA and chromatin remodeling; (4) regulating transcription factor activity and affecting their binding to gene promoter regions; (5) affecting covalent modifications of RNAs; (6) influencing alternative splicing of RNAs; (7) altering the subcellular localization of RNAs; and (8) altering the stability of RNAs [14,15].
With the development of high-throughput technologies and various genomics approaches, we are now better equipped to comprehend the biological characteristics and disease expression profile of depression on a genome-wide scale and to construct the global expression network.To date, 21,183 lncRNAs from Homo sapiens have been included in the National Center for Biotechnology Information database (https://www.ncbi.nlm.nih.gov/).Databases for querying and analyzing lncRNAs are constantly emerging.Examples include, LNCipedia (https://lncipedia.org/),RNAcentral (https://rnacentral.org/), and LncRNADisease (http://www.cuilab.cn/lncrnadisease).An increasing number of studies have reported altered lncRNA expression profiles in both brain regions and the blood of patients with depression [16][17][18][19].In this article, we focus on a systematic review of the role of lncRNAs in depression, and aim to generate novel insights for objective diagnostic marker identification, efficacy prediction, and antidepressant therapy development [15].Through PubMed and the Web of Science Library, we conducted an online search for all research published up to March 2023.The databases were searched by using the terms "lncRNA", "long noncoding RNA", and their combinations with "major depression", "major depressive disorder", and "depression".The language was limited to English.

LncRNAs Involved in Competing Endogenous RNA (ceRNA) Networks
The ceRNA hypothesis was proposed in 2011 [20].MiRNAs are negative regulators of gene expression since they can diminish the stability of target RNAs or repress their translation via complementary pairing with the 3 ′ untranslated region (3 ′ UTR) of mRNAs [21,22].If a lncRNA and a mRNA have high sequence homology, i.e., a lncRNA and mRNA have the same miRNA response element, then the lncRNA can competitively bind the miRNA and reduce its intracellular content, thereby reducing the repressive effect of the miRNA on its target gene.
LncRNAs also have multiple targets, and a single lncRNA molecule may inhibit multiple target miRNAs.In addition to the miR-10b/BDNF pathway previously mentioned, the lncRNA GAS5, for instance, may also be implicated in the regulation of gene expression in depression through the microRNA-26a/EGR1 axis [26].MiR-26a targets EGR1, while the lncRNA GAS5 can specifically bind miR-26a.In mice with depressive-like behavior, EGR1 suppresses the activation of the PI3K/AKT pathway to induce the release of inflammatory substances and the apoptosis of hippocampal neurons.Therefore, lncRNA GAS5 reduces the inhibitory effect of miR-26a on EGR1 by acting as a ceRNA, inhibiting PI3K/AKT pathway activation and protecting hippocampal neurons from damage in mice with depressive-like behavior.This relationship between one lncRNA and multiple miRNA targets was also predicted by bioinformatics analysis [27].For example, Chen et al. [27] identified that seven miRNAs (miR-425, miR-486, miR-28-5p, miR-29b, miR-100, miR-125b and miR-320) showed potential matching sequences with the lncRNA Gm26917.
In depression, the targets regulated by lncRNAs through their ceRNA activity are involved in several processes, including neurotrophic processes [23], immunoinflammatory processes [26], glutamatergic processes [28], and methylation modifications [29].In the prefrontal cortex of chronic unpredictable mild stress (CUMS) rats, miR-29b-3p expression was elevated after ketamine treatment, leading to a decrease in the expression of the glutamate metabotropic receptor GRM4 [28].Based on the inhibition of miR-29b-3p by lncRNA Gm26917, lncRNA Gm26917 is a crucial regulator of fluoxetine and ketamine and a potential target for depression treatment [30].Ding X et al. [29] found that lncXR_351665, as a miR-152-3p sponge, upregulated the DNA methyltransferase DNMT1 to promote the development of chronic pain-induced depression.In summary, miRNAs and their target genes, as downstream targets of lncRNA regulation, establish a complex ceRNA regulatory network together with lncRNAs.LncRNAs are involved in the progression of depression through multiple targets and multiple pathways.A total of 13 lncRNAs (involving 16 ceRNA regulatory axes) are summarized in Table 1.

Interaction and Cooperation between LncRNAs and Epigenetic Modifications
Epigenetic modifications, primarily in the form of DNA methylation, histone modification, and chromatin remodeling, lead to heritable changes in genetic phenotypes and gene expression that do not involve changes in DNA sequences [45].DNA methylation modifications occur mainly on cytosines in CpG islands [46].Another important type of epigenetic change is histone modification.In general, histones can undergo different types of covalent modifications (e.g., methylation and acetylation) catalyzed by various histone-modifying enzymes [46].It is commonly accepted that methylation represses gene transcription, whereas acetylation relaxes the chromatin structure by charge neutralization and enhances transcription.LncRNAs can function as molecular scaffolds, molecular decoys, molecular guides, etc., either to regulate epigenetic processes or as targets for epigenetic modifications [47,48].
Changes in epigenetic modifications (including the addition and removal of groups) interact and coregulate lncRNAs in complex disorders in at least three different ways.First, the alterations of covalent modification in the lncRNA locus result in changes in the biochemical properties or chromatin structure of the DNA sequence.This affects the binding of RNA polII or other transcription factors and alters lncRNA transcription.For example, DNA hypermethylation occurs in a CpG island of a specific gene, and the addition of methyl groups to histones in the promoter region leads to chromatin remodeling [49].This not only decreases the expression of the protein coding gene but also inhibits the transcription of antisense lncRNAs of the encoding gene [49].In addition to antisense lncRNAs, intergenic lncRNAs may also be affected by methylation.If the CpG island in the protein-coding gene is embedded in the promoter of the lncRNA, the transcription of the lncRNA decreases.Second, lncRNAs can mediate covalent modification-related enzymes to change the epigenetic modification of target genes, thus affecting gene expression [50].LncRNAs can recruit or activate methyltransferases to increase the DNA methylation level of their target genes [51].They can also mediate histone-modifying enzymes to covalently modify histones in the promoter regions of the genes [52], change the biochemical properties or chromatin conformation of the genes, affect the binding of transcription factors to the genes and switch the expression of the genes on or off.In mice, the lncRNA BDNF-AS was identified to block BDNF transcription by recruiting the histone methylation transferase EZH2 [53].By recruiting PRC2, the lncRNA Xist can initiate chromosomal CpG island methylation.This, in turn, suppresses the expression of genes on the X chromosome [54] and leads to gender-specific differences in susceptibility to neurological and psychiatric disorders [55].Third, lncRNAs themselves serve as targets for methylation.m6A is one of the most common types of methylation on lncRNAs, and this modification is formed by the addition of a methyl group to an adenosine base through a reaction catalyzed by the methylases METTL3 and METTL14.m6A-modified lncRNAs are recognized by reader proteins, such as the YTH family, which induce RNA binding proteins to form RNA-protein complexes, thus regulating mRNA expression [49].Clearly, in the first two regulatory mechanisms, epigenetic modifications occur on DNA or histones, causing changes in mRNA transcription levels.However, in the third mechanism, modifications occur on RNA and are posttranscriptionally regulated.

LncRNAs Associated with m6A Modification in Depression and Prediction of Their Functions
Although an increasing number of studies have noted the effects of altered methylation modifications and lncR-NAs on depression, their interactions and mechanisms of action in depression are still unclear.Due to the availability of data, we focused on the mechanisms of lncRNA regulation associated with m6A modifications in depression.We identified the lncRNAs associated with m6A modifications and further explored the potential biological functions of these lncRNAs by using the transcription profile GSE217811 [containing data for 10 patients with major depressive disorder (MDD) and 10 healthy control individuals] from the Gene Expression Omnibus (GEO, online: http://www.ncbi.nlm.nih.gov/geo/)database.
Via the limma package of R software, 14137 differentially expressed lncRNAs were identified from the dataset (p < 0.05).Generally, genes with similar expression pro- files are considered to be potentially involved in parallel biological processes; thus we further screened 206 lncRNAs with a coexpression relationship with m6A modificationrelated genes from the set of differentially expressed lncR-NAs (Table 2).Finally, mRNAs were screened by the similarity matrix of the mRNA-lncRNA expression profile (p < 0.05), and the biological significance of the lncRNAs was recognized by the functional annotation of the mRNA.
Functional annotation analysis showed that these mR-NAs with similar expression profiles to those of lncR-NAs were mainly enriched in 116 Gene Ontology (GO) terms and 35 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways (p < 0.05) (Fig. 1).Altered neuronal synapse number and function and impaired synaptic plasticity are common features of depression [44,56].The m6A modification-related lncRNAs were shown to act at targets associated with the synaptic microenvironment, with enrichment in terms such as postsynaptic specialization, neuron-to-neuron synapses, asymmetric synapses, and postsynaptic density, according to functional annotation analysis (Fig. 1b).This suggests that alterations in lncR-NAs and their m6A modifications may have an impact on the synaptic microenvironment and thus contribute to the development of depression.The lncRNAs were also enriched in molecular functions or biological processes, such as the regulation of I-κB kinase/NF-κB signaling, anion transport, dephosphorylation, and ubiquitin-like protein ligase activity (Fig. 1a,c).Numerous studies have demonstrated the involvement of these molecular functions or biological processes in neurological disorders, even providing direct evidence of their association with depression [56][57][58][59][60][61].The functional annotation analysis of lncRNAs in this paper shows the relationship between lncRNAs and m6A modifications and the abovementioned molecular functions or biological processes, reiterating their roles in depression.
According to KEGG pathway analysis, m6A modification-associated lncRNAs may be related to the pathways of endocytosis, tight junctions, Salmonella infection, activation of chemoattractant receptors, Wnt signaling pathway, and PPAR signaling pathway (Fig. 1d).Among these pathways, the PPAR signaling pathway has received attention in the study of neurological diseases.PPARs have three subtypes, PPARα, PPARβ, and PPARγ.Drug molecules can induce a neuroprotective microglial phenotype in the hippocampus via the PPAR-γ pathway, resulting in the amelioration of chronic mild stress (CMS)-induced depression-like behavior [62].

The Effect of SNPs on LncRNAs in Depression
Single nucleotide polymorphisms (SNPs) are DNA sequence polymorphisms resulting from single nucleotide variations at the genomic level.More than 90% of all known polymorphisms are SNPs, making it the most prevalent heritable variation in humans [63].SNP loci have been used in genome-wide association studies (GWAS) and have become the major route for the discovery of complex genetic mechanisms of disease.Depression has complex genetic variations, with numerous SNPs identified across the genome.

The Effects of SNPs on LncRNAs and Their Cooperation in Diseases
There are at least two effects of SNPs on lncRNAs: SNPs in nonlncRNA loci that indirectly affect lncRNA transcription and SNPs in lncRNAs that directly regulate lncRNA expression.First, SNPs in genes encoding proteins (e.g., transcription factors) may lead to functional changes in the structure of the encoded protein and enhance or weaken its capacity to bind target lncRNAs.These alterations may either improve disease phenotypes or contribute to disease progression by mediating changes in lncRNA expression levels [64,65].Second, SNPs in lncRNAs can become switches for lncRNA gene expression.Mutations in the lncRNA regulatory region change the binding abil-ity of nucleic acid sequences to transcription factors or other protein factors, thus activating/enhancing or blocking/decreasing the expression of the lncRNA [66].

SNPs in LncRNAs Involved in Depression
The results from clinical cohort studies have shown that polymorphisms in depression risk genes are significantly related to the pathogenesis of depression and the efficacy of antidepressants.In a cohort study that consisted of people with MDD who attempted suicide, people who did not attempt suicide, and healthy subjects, Zheng et al. [67] identified 83 SNP loci in EPHX2 and P2X2.EPHX2 and P2X2 may mediate the antidepressant-like effects of ATP.Among these SNP loci, rs9331949 is located in lncRNA NONHSAT215593.1 (Table 3, Ref. [67][68][69][70][71][72][73][74][75][76][77], querying the lncRNASNP v3 database, http://gong_lab.hzau.edu.cn/lncRNASNP3/#!/)[78].Namvar A et al. [68] fully discussed the relationship between the SNP sites on lncRNA ANRIL and the risk of MDD were in different inheritance models.Two SNPs, rs1333045 and rs1333048, were verified as risk loci [68].SNP loci associated with major depression in Europeans individuals were first reported in a study by Hyde CL et al. [69].This study investigated a combined cohort of 130,620 lifetime major depression cases and 347,620 controls and established 17 genome-wide SNPs in 15 independent gene regions, including rs1475120 in the intron of LIN28B (aka NONHSAT251362.1, etc.).Retrieval of SNPs in the lncRNASNP2 database revealed that rs1475120 is located in the linkage disequilibrium (LD) region and affects the binding of a lncRNA (NONHSAT207767.1)to miRNAs (Table 3).
Genes related to neurodevelopment, neuroplasticity, and neurotransmission, such as DISC1, TSNAX, and DAOA, have attracted considerable attention in depression research.Allelic variations in these genes are more likely to be identified as risk SNPs and potential antidepressant targets.Arias B et al. [70] investigated the relationship of 13 polymorphic loci in DISC1-TSNAX and DAOA with MDD and citalopram efficacy.The results revealed associations between MDD and rs3738401 in DISC1 and rs1615409 and rs766288 in TSNAX (p = 0.004, p = 0.0019, and p = 0.008, respectively).Among them, rs3738401 is located in a lncRNA (NONHSAT150722.1)(Table 3).Another depression susceptibility gene of long-standing interest, BDNF, also has multiple SNPs.Multiple novel SNP loci in the BDNF sequence were identified by a deep sequencing effort [71].The association analysis of MDD patients and control individuals revealed that six SNPs were associated with MDD (rs12273539, rs11030103, rs6265, rs28722151 rs41282918, and rs11030101).Among them, three SNPs, rs6265, rs28722151, and rs11030101, are located in lncR-NAs.Whether these allelic variants regulate BDNF expression by mediating lncRNAs needs further verification (Table 3).

Cis or trans Regulation of LncRNAs is Involved in Depression
LncRNAs can not only interact with nucleic acid sequences by base complementary pairing to form RNA-DNA complexes but also form relatively complex and variable spatial structures (compared to those formed by other small ncRNAs) to recruit or act as scaffolds to bind other proteins to form RNA-protein complexes.Thus, lncRNAs have flexible and diverse mechanisms of controlling gene expression.Numerous studies have indicated this feature and regulatory mechanism of lncRNAs.
Using RNA pull-down, chromatin immunoprecipitation, and RNA immunoprecipitation approaches, these studies have shown that lncRNAs bind to biomolecules such as transcription factors, proteins, mRNAs and DNA and form gene regulatory networks, revealing the biological functions and mechanisms of lncRNAs.According to the position of lncRNAs relative to the target genes, the regulation mode of lncRNAs with respect to the target genes can generally be classified into two categories: cis and trans regulation [79].Next, we discuss the mechanism of lncRNAs in depression from two perspectives, cis and trans regulation.

Cis and trans Regulation of LncRNA
Cis regulation by lncRNAs is typically based on the observation that lncRNAs have close physical proximity to their target genes.First, lncRNAs have the ability to bind directly to the 5 ′ -UTRs of adjacent genes and inhibit or pro-mote the expression of the genes by blocking or recruiting transcription factors, such as RNA polII [80][81][82] (Fig. 2a).LncRNAs can also contribute to looping cross-talk with chromatin in adjacent genes to regulate gene expression.In some cases, lncRNAs do not directly participate in the reg-ulation of gene expression but share the same transcription factors, including RNA polII, with adjacent genes.When transcribed, lncRNAs can compete with adjacent gene promoters to bind RNA polII or affect the local chromatin state and transcription factor binding to the promoter and enhancer regions [83][84][85] (Fig. 2b).There is another species of lncRNAs whose sequences contain DNA regulatory elements, such as enhancers.These DNA regulatory elements regulate the expression of the adjacent genes independent of lncRNA transcription [83].That is, the RNA transcripts of the lncRNA genes have no effect on the adjacent genes, but mutations in the DNA sequence of the lncRNA genes or elimination of this sequence alters the expression of the adjacent target genes [83] (Fig. 2c).In summary, it is clear that cis regulation by lncRNAs has two distinct features.First, the lncRNA and the target gene are in close proximity; second, the lncRNA directly or indirectly affects the regulatory regions of the target gene, which regulates its transcription.Via trans regulatory mechanisms, lncRNAs have a variety of potential effects on the spatial conformation of distal genes.Transcribed lncRNAs can leave the locus to bind to target genes and act as scaffolds or decoys to recruit proteins to synergistically regulate gene expression [86,87] (Fig. 2d).The way a lncRNA functions is to some extent influenced by its cellular localization.LncRNAs can affect the structure of the nucleus.The lncRNAs in the nucleus can be recruited into nuclear speckles to form spliceosomes with numerous cleavable proteins to regulate alternative splicing of RNA and maintain the normal function of organelles in the nucleus [88,89] (Fig. 2e).The last species of lncRNAs can also perform trans regulatory functions by influencing trans acting factors or other RNA molecules with regulatory functions (Fig. 2f).In conclusion, the above three types of lncRNA trans regulatory modes share the same regulatory characteristics.The first is, the ability to affect genes that are distant from their own loci, and the second is the ability to regulate target genes at the transcriptional or posttranscriptional level.

Cis or trans Regulation of LncRNAs in Depression
Cis or trans regulation of lncRNAs is widespread in the nervous system.For example, the KALRN gene encodes several protein isoforms that play key roles in dendritic arbors and spine remodeling and synaptic plasticity.Dysregulation of the KALRN gene has been implicated in various neurological disorders.LncRNA Kalnc2, arising from the 5 ′ end of the KALRN locus, cis regulates KALRN transcripts in mouse neuronal cells [90].Important strategies for treating depression include boosting neurotrophic factor expression and promoting neural regeneration [91].Perry et al. [92] documented that the lncRNA Silc1 is highly expressed in regenerated neurons and activates dormant RNA pol on the promotor of the transcription factor Sox11 by acting in cis.Then, Sox11 is activated to promote neuronal regeneration [92].The prefrontal cortex and hippocampus tend to exhibit dysfunction and aberrant gene expression in depression.Zhang et al. [93] found that the expression of the lncRNA GM16638-201 in the hippocampus and prefrontal cortex of CUMS mice was high and inhibited the 14-3-3Ɛ pathway.Nine genes were predicted to be regulated by GM16638-201.Seven of these genes (Elmo2, Satb1, Hnrnpul1, Sipa1l3, Mapt, Tada3, and Sgip1) were regulated in trans by the lncRNA GM16638-201, and two genes (StarD5 and IL-16) were regulated in cis (Table 4, Ref. [93,94]).In depression, lncRNAs also regulate interferon expression in cis.We clarify the mechanisms and provide specific instances in the following section.

LncRNAs Regulate the Immune System in Depression
The immune-inflammatory hypothesis is one of the explanatory hypotheses for the pathogenesis of depression.This hypothesis proposes that inflammation is crucially in-
[93] volved in the onset of depression or that depression is an immune system-mediated warning to the body.

Satb1 trans
Significantly elevated expression levels of different types of proinflammatory cytokines in cerebrospinal fluid and peripheral blood are common in patients with depression [95,96].The reason for this may be that the HPA axis, which secretes a number of hormones and neurotransmitters to regulate peripheral immunity, becomes more active in response to stress [97].The immune system responds quickly and increases the levels of inflammatory mediators, including cytokines.Immune messages are transmitted between the peripheral and central neural systems by inflammatory cytokines, altering the central nervous system or causing corresponding behavior changes [98].Since Smith first proposed in 1991 that cytokines could be involved in depression [99], inflammatory cytokines have been found to induce depression-like behavior [95,100].For example, proinflammatory cytokines, such as IL-2 and IL-16, affect the function of serotonergic neurons by inducing dioxygenases, resulting in a depressive state in the body [101].Clinical studies have found that patients develop MDD symptoms during interferon treatment, and the risk of depression after interferon treatment is 30%-70% regardless of the treatment indication [102].In a study by Zhou et al. [94], several lncRNAs were identified, and the overlapping or antisense genes of these lncRNAs, such as IRF2, LY6E, and HMBOX1, were shown to be associated with interferon transcription, activation, and signal transduction (Table 4).
IRF2 is antisense to the lncRNA RP11-326I11.3and encodes a transcription factor (TF) involved in interferon signal transduction.LY6E is antisense to the lncRNA RP11-273G15.2and is an interferon-stimulated gene with immunomodulatory function.The lncRNA CTD-2647L4.4 is a sense intron of HMBOX1, which encodes a TF involved in transcriptional repression, including inhibition of interferon genes [103][104][105][106][107]. Therefore, these overlapping proteincoding genes or antisense genes of these differentially expressed lncRNAs were predicted to be potential targets of lncRNA cis regulation by Zhou et al. [94].In short, lncR-NAs may be involved in depression by cis regulating the expression of these interferon-related genes.Recent research has revealed that lncRNAs may regulate proinflammatory cytokines to lessen the symptoms of depression [108,109].Sun et al. [110] showed that lncRNA MSTRG.81401significantly reduced the expression of the cytokines TNF-α and IL-1β in animal models and alleviated diabetic neuropathic pain and depressive behavior in rats.Although there is no direct evidence yet that lncRNAs are involved in depression mediated by immune factors, an increasing number of studies have shown a potential regulatory relationship between lncRNAs and inflammatory factors in this disease.For example, in macrophages, the lncRNA THRIL can activate the transcription of TNFα by binding to its promoter [111], and TNFα mediates depression like behavior caused by stress induced GSK3 activation in a learned helplessness mouse model [112].Therefore, it was suggested that there may be a potential THRIL-TNFα axis in depression, but this requires further experimental verification.We have summarized more potential lncRNA-cytokine regulatory axes in Supplementary Table 1.
Inflammasomes are polymeric protein complexes that resemble apoptotic bodies and have the ability to cause inflammation in the cytoplasm [113].LncRNAs may also be involved in MDD by interfering with the formation of inflammasomes.The role of lncRNA Gm14205 in postpartum depression (PPD) was described by Zhu et al. [114].The lncRNA Gm14205 may palliate PPD by inhibiting oxytocin receptor activation and inducing activation of NLRP3 inflammatory vesicles in astrocytes.
The gut-brain axis affects the nervous system through the interaction between the vagal nervous system and the intestinal immune system [115].Evidence of crosstalk between the gut-brain axis and the HPA axis was demonstrated by Misiak B et al. [116].Dyshomoeostasis of the gut flora severely interferes with central nervous system neurotransmission through the HPA axis and vagal afferent nerve fibers, accompanied by local inflammation that exacerbates anxiety or depressive behavior [117,118].There is no direct experimental evidence to confirm the interactions between lncRNAs and the gene regulatory network of the gut-brain axis in depression.However, recent artificial intelligence-mediated biological analysis has shown that multiple lncRNAs, including HOTAIR, MEG3, GAS5, and TUG1, may be hub factors in the lncRNA regulatory network and are influenced by improvements in the gut environment in animal models of depression [119].

Conclusion
The current state of depression treatment is characterized by the lack of knowledge of the pathophysiology and objective diagnostic indicators of depression, as well as the limited availability of drugs, the slow onset or even ineffectiveness of drugs, the high relapse rate, and the harmful side effects of drugs [120,121].It is crucial to understand the pathogenesis of depression and develop new diagnostic biomarkers and therapeutic targets.The abundant lncRNA expression profile data provide us with new tools.Considering the high heterogeneity of complex diseases such as depression, future research may need to build a good framework with multiple dimensions.Since alterations in gene expression lead to the remodeling of central nervous system structure, immunoregulation, and neurotransmission, the establishment of multidimensional and efficient diagnostic models by combining lncRNAs with other indicators, such as imaging features, protein profiles, and metabolite profiles is a promising strategy [12].Constructing a diagnostic classifier by the nomothetic network psychiatry (NNP) approach may be a useful attempt.Maes et al. [122] integrated and ensembled multiple factors into a cause-to-outcome model by means of NNP in a study of MDD.Factors integrated in this study included genome and environmentome features (psychosocial aspects, contextcentered hermeneutic data), brainome features, cognitome features, symptomatome features (different symptom domains or clinical phenotypes) and descriptive psychopathological assessments.According to the NNP, the diagnostic gold standard DSM/ICD has been challenged, and multiple false dogmas are thought to exist in mood disorder research.NNP has been attempted in studies of MDD, bipolar disorder, schizophrenia, and other disorders [122][123][124][125].However, to date, no study has provided both lncRNA expression profiles and abundant other information for modeling NNP.This is one of the future endeavors to look forward to.Furthermore, as we have reviewed before, lncR-NAs may be involved in the development of depression through various mechanisms, such as ceRNA activity, epigenetic regulation, inflammation and immunity, and single nucleotide polymorphisms.The bioinformatics analysis performed in this review also suggests potential relationships between lncRNAs and methylation modifications and SNPs in depression.However, research on the mechanisms of action of lncRNAs in depression is still in its infancy.Additionally, most studies only show their correlation with the occurrence of depression by statistical analysis of differentially expressed lncRNAs and predict the regulatory mechanism by bioinformatics tools.Therefore, providing clear and powerful evidence to explain the role of lncRNAs in depression through molecular biology experimental approaches should be one of the future directions of subsequent work.

Fig. 1 .
Fig. 1.The top 20 molecular functions and pathways in GO and KEGG analyses of lncRNAs related to m6A from the transcriptional profile of GSE217811.(a) Biological processes in which m6A-related lncRNAs are involved.(b) Cell components in which m6A-related lncRNAs are involved.(c) Molecular functions in which m6A-related lncRNAs are involved.(d) Biological signaling pathways in which m6A-related lncRNAs are involved.GO, Gene Ontology; KEGG, Kyoto Encyclopedia of Genes and Genomes.

Fig. 2 .
Fig. 2. The cis and trans regulation modes of lncRNAs.(a-c) The cis regulation modes.(d-f) The trans regulation modes.(a) LncRNA binds directly to the 5 ′ -UTR of adjacent genes and forms looping crosstalk to regulate gene expression.(b) LncRNA loci share RNA polII with adjacent genes.Thus, lncRNAs compete with gene promoters and inhibit their expression.(c) LncRNA loci contain the regulatory elements of adjacent genes, such as enhancers, in which the mutations alter gene expression.(d) LncRNA leaves the locus to combine with the distant gene and act as scaffolds to recruit proteins to synergistically regulate gene expression.(e) LncRNA in the nucleus is recruited into nuclear speckles to form spliceosomes and regulate the alternative splicing of RNA.(f) LncRNA combines with the 3 ′ UTR binding proteins of the distal gene mRNA, thereby accelerating mRNA degradation.TF, transcription factor.