**1. Introduction**

Endometriosis is a chronic inflammatory disorder defined by endometrial-like lesions growing ectopically outside of the uterus that affects many reproductive-age women worldwide. The disease has heterogeneous symptoms that may not be specific to the disease, such as different types of chronic gynecological pain and reduced fertility. The cause of the disease remains unclear, but lesions are thought to originate from endometrial cells that escape the uterus [1], although the presence of rare endometriosis-like lesions in males supports a trans-differentiation origin [2]. Endometriosis is thought to be an immunological disease, first because lesions must evade the immune system in order to establish and develop, and second because the inflammatory nature of the disease accounts for many of the symptoms [3]. Additionally, a meta-analysis has found that there is some association between endometriosis and a risk for developing an autoimmune disease [4]. Treatment options for the disease remain limited to laparoscopic surgery to remove lesions and hormone-based treatments that are not compatible with pregnancy [3]. Given that diagnosis is often delayed due to the non-specific symptoms and that there are limited treatment options, there is a need to better understand the molecular pathogenesis of the disease in order to identify key players that may be used as biomarkers for diagnosis or as targets for new treatments. One class of molecules that may play a role in the disease are long non-coding RNAs (lncRNAs).

**Citation:** Hudson, Q.J.; Proestling, K.; Perricos, A.; Kuessel, L.; Husslein, H.; Wenzl, R.; Yotova, I. The Role of Long Non-Coding RNAs in Endometriosis. *Int. J. Mol. Sci.* **2021**, *22*, 11425. https://doi.org/10.3390/ ijms222111425

Academic Editor: Antonio Simone Laganà

Received: 22 August 2021 Accepted: 19 October 2021 Published: 22 October 2021

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LncRNAs are a class of genes that since the advent of high-throughput sequencing technology have been revealed to be much more numerous than was previously realized. Currently over 16,000 human lncRNAs are annotated by the GENCODE project, while some other studies have indicated that the total number may be over 100,000 [5]. Although most of these lncRNAs remain uncharacterized, an increasing number have been shown to have a biological function, often involved in gene regulation [6]. LncRNAs remain relatively under investigated in endometriosis, but given their roles in development and disease in other contexts [7], it is reasonable to assume that there may be lncRNAs that also play a role in endometriosis.

LncRNAs may exert their function in either the nucleus or the cytoplasm via a variety of mechanisms. In the nucleus, lncRNAs may act as epigenetic gene regulators by recruiting chromatin remodeling or modification complexes to target gene promoters either in *cis* (Figure 1a) [8] and/or in *trans* to activate or suppress their transcription (Figure 1b) [9]. LncRNAs can act as decoys of specific chromatin modifiers by sequestering them from the promoters of target genes (Figure 1c) [10]. In other contexts, lncRNAs may act as transcriptional regulators by competing with a transcription factor for binding DNA and/or by binding its DNA binding domain (Figure 1d) [11]. LncRNAs have also been associated with the regulation of pre-mRNA alternative splicing in the nucleus, thereby affecting which isoforms predominate (Figure 1e) [12]. In the cytoplasm, lncRNAs are involved in post-transcriptional regulation processes that can affect the stability of transcripts (Figure 1f) [13] or whether a transcript is translated into a protein or not (Figure 1g) [14]. LncRNAs can also be involved in the modulation of cell signaling pathways by binding to signaling proteins and affecting their activation state (Figure 1h) [15]. Finally, a common mechanism whereby lncRNAs are thought to affect mRNA abundance is by acting as so-called "sponges" of miRNAs to reduce miRNA-mediated degradation. Here, lncRNAs may share miRNA target sequences with mRNAs, thereby reducing miRNA availability to target mRNAs (Figure 1i) [16,17].

These studies show that lncRNAs can act at multiple subcellular sites to affect various aspects of cell biology, although in most cases they affect either transcription or processing of mRNAs and their steady state levels in the cell. That is, in a broad sense, they regulate other genes. An increasing body of literature implicates abnormal expression of specific lncRNAs in disease, particularly in different types of cancer [18], but also in a variety of other diseases including neural disorders [19], cardiovascular disease [20], and diabetes [21]. Evidence for the involvement of individual lncRNAs in the pathogenesis of these diseases ranges from a correlation with dysregulated lncRNA expression to detailed mechanistic studies that indicate a functional role in the disease. The implication from these studies and others is that lncRNAs are important players in the pathogenesis of many diseases, suggesting that there may be lncRNAs that play a role in endometriosis. Furthermore, a number of studies in have shown that lncRNAs can either be regulated by estrogendependent enhancers [22] or that lncRNAs can regulate estrogen receptor expression [23]. As endometriosis is an estrogen-dependent disease [3], these studies give further impetus to investigate the role of lncRNAs in the disease. Given this evidence for the role of lncRNAs in other contexts, in this review, we aim to provide a comprehensive picture of the current state of knowledge over the role of lncRNAs in endometriosis.

**Figure 1.** Description of the general mechanisms of the lncRNA actions in the nucleus (**a**–**e**) or in the cytosol (**f**–**i**). (**a**) Regulation in *cis* by lncRNA *ANRIL*, which mediates polycomb repressive complex (PRC) 1 and 2 recruitment to the promoter of the neighboring *CDKN2A* and *CDKN2B* genes, thereby controlling their expression [8]. (**b**) Regulation in *trans* by *ANRIL*, which acts through Alu sequences to recruit PRC1 and PRC2 complexes to distant targets [9]. (**c**) The embryonic stem cell–specific lncRNA *lncPRESS1* sequesters the histone deacetylase Sirtuin 6 (SIRT6) from the promoters of numerous pluripotency genes. *LncPRESS1* keeps histone H3 acetylated, thereby activating the transcription of pluripotency genes. During differentiation or following depletion of *lncPRESS1*, SIRT6 localizes to the chromatin, blocking the transcription of pluripotency genes [10]. (**d**) The lncRNA *GAS5* folds into a DNA-like structure and binds to the glucocorticoid receptor (GR), thereby inhibiting its transcriptional activity [11]. (**e**) The nuclear-retained lncRNA *MALAT1* can regulate alternative splicing by modulating the phosphorylation of the SR splicing factor [12]. (**f**) In the cytosol, the lncRNA *urothelial carcinoma associated 1* (*UCA1*) stabilizes *CDKN2A-p16* mRNA by sequestering the heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) [13]. (**g**) LncRNA *LBCS* suppresses the androgen receptor (AR) translation efficiency by forming a complex with hnRNPK and *AR* mRNA [14]. (**h**) The *lncRNA for kinase activation* (*LINK-A*) directly interacts with the AKT pleckstrin homology domain and PIP3 facilitating AKT–PIP3 interaction and consequent enzymatic activation [15]. (**i**) The lncRNA *PVT1* sponges *miR-503* to upregulate *ARL2* expression in cervical cancer [17].
