*4.1. Chromatin Remodeling and Transcriptional Control by lncRNAs in Endometriosis*

The HOTAIR lncRNA is known as a critical regulator of HOX gene expression. Maintaining appropriate expression of genes within the HOX-gene network has been shown to be critical for endometrial homeostasis during embryonic implantation, and alterations in HOXA10 and HOXA11 expression have been associated with endometriosis-associated infertility [49,50]. Mechanistically, *HOTAIR* interacts with the PRC2 or REST/CoREST chromatin remodeling complex to guide the recruitment of H3K27 tri-methylation or H3K4 demethylation at target gene loci resulting in target gene silencing [51]. As described above, it has been shown that genetic variations at SNPs sites in *HOTAIR* are relatively frequently detected in patients with endometriosis [30]. These genetic changes alter the thermostability of mature *HOTAIR* leading to epigenetic silencing of *HOXD10* and *HOXA5* genes and are associated with more advanced endometriosis [30].

Overexpression of the lncRNA *AFAP1-AS1* has been shown to be associated with ovarian endometriosis [33]. In another example of direct transcriptional regulation by an lncRNA in endometriosis, *AFAP1-AS1* directly activates expression of EMT-related transcription factor ZEB1 in vitro [47]. ZEB1 has been previously shown to be involved in 17β-estradiol-induced EMT in endometriosis [52], indicating a possible mechanism by which *AFAP1-AS1* could affect endometriosis.
