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Hossain, M.J.; Nyame, P.; Monde, K. Long Terminal Repeat Promoters of Endogenous Retroviruses. Encyclopedia. Available online: (accessed on 16 April 2024).
Hossain MJ, Nyame P, Monde K. Long Terminal Repeat Promoters of Endogenous Retroviruses. Encyclopedia. Available at: Accessed April 16, 2024.
Hossain, Md Jakir, Perpetual Nyame, Kazuaki Monde. "Long Terminal Repeat Promoters of Endogenous Retroviruses" Encyclopedia, (accessed April 16, 2024).
Hossain, M.J., Nyame, P., & Monde, K. (2024, March 13). Long Terminal Repeat Promoters of Endogenous Retroviruses. In Encyclopedia.
Hossain, Md Jakir, et al. "Long Terminal Repeat Promoters of Endogenous Retroviruses." Encyclopedia. Web. 13 March, 2024.
Long Terminal Repeat Promoters of Endogenous Retroviruses

Endogenous retroviruses (ERVs) became a part of the eukaryotic genome through endogenization millions of years ago. Moreover, they have lost their innate capability of virulence or replication. Nevertheless, in eukaryotic cells, they actively engage in various activities that may be advantageous or disadvantageous to the cells. The mechanisms by which transcription is triggered and implicated in cellular processes are complex. Owing to the diversity in the expression of transcription factors (TFs) in cells and the TF-binding motifs of viruses, the comprehensibility of ERV initiation and its impact on cellular functions are unclear. Currently, several factors are known to be related to their initiation. TFs that bind to the viral long-terminal repeat (LTR) are critical initiators. 

endogenous retrovirus transcription factor long-terminal repeat

1. HERV LTRs Are Required for the Transcription of Neighboring Genes

LTRs are essential for transcription in multicellular organisms [1][2][3]. Based on the LTR sequence, HERV-K (HML-2) LTR is classified into LTR5A, LTR5B, and LTR5Hs subtypes [4]. Indeed, the HERV-K core promoter elements (U3, R, and U5) are essential to make the promoter functional [5][6][7]. As every provirus has undergone distinct mutations over the course of millions of years, these LTR sequence modifications may affect the binding of TFs to LTR-binding sites, which in turn may lead to the distinctive expression of HML-2 [8]. Chromatin state analysis has revealed that different HERV LTRs enriched in the enhancer regions are distinct across cell types [9]. The expression of neighboring genes from ERV LTR was analyzed by the activation/silencing of the HERV-K LTR5Hs using CARGO with CRISPR activation (CRISPRa) or interference (CRISPRi) [10]. The results indicated that the chromatin state of its neighboring genes is remarkably changed and that LTR5Hs acts as distal enhancer or suppressor to regulate the expression of at least 275 genes [10]. Furthermore, the expression of neighboring genes, which are located either proximal or distal within a range of ~200 kb from LTR5Hs, is regulated by LTR5Hs activation or silencing [10]. In summary, because LTRs affect the expression of neighboring genes within a 200 kb range, identifying the elements involved in transcription from the LTRs may allow us to determine causal relationships with various ERV-related diseases.

1.1. TFs Associated with LTR Activation of HERV-K

p53 directly upregulated the promoter activity of LTR5Hs rather than LTR5A and LTR5B in cervical carcinoma (HeLa) and HEK293T cells [4]. Luciferase reporter and ChIP assay results proved that the two binding sites for p53 on LTR5Hs are important for upregulating transcription and activating other LTRs [4]. Although p53 plays an important role in suppressing cancer progression, the mechanism by which it activates HERV-K remains unclear. A recent study reported that the presence of anti-HERV-K Env antibodies is important for lung cancer immunotherapy [11]. Thus, if p53-mediated HERV-K activation is involved in lung cancer immunotherapy, this will be a topic for future research.
HERV-K LTR5Hs (HERV-K113) has a full-length ORF and is located on chromosome 19p13.11 [12]. The prevalence of HERV-K113 mRNA is higher (29%) than that of other HERVs in various cancer cells, particularly teratocarcinoma cells [12]. Specific TFs are necessary to activate this LTR-driven genome, which include Sox2, Oct4, and Nanog (Table 1) [13][14][15]. However, the individual expression of Oct4 and Nanog is insufficient to activate HERV-K LTR5Hs [14], while the combined expression of Oct4 and Nanog, along with Sox2, markedly enhances the transactivation capability [14]. Historically, Sox2 has been shown to control cancer stem cell maintenance and self-renewal, fostering oncogenic signaling [16][17][18]. Interestingly, HERV-K expression is significantly upregulated in germ cell tumors, melanomas, and ovarian cancers compared to that in healthy tissues [19][20][21][22]. These findings suggest that the transactivation of HERV-K LTR5Hs by Sox2 is involved in numerous malignant tumors.
Table 1. List of human endogenous retroviruses, their transcription factors, chromosomal location, and associated functions. HERV: human endogenous retrovirus; ERV: endogenous retrovirus; DUX: double homeobox 4; HIF: hypoxia-inducible transcription factor; NF-κB: nuclear factor-κB; YY1; Yin Yang 1; chr: chromosome; AT/RT: atypical teratoid rhabdoid tumor; ALS: amyotrophic lateral sclerosis; IFN: interferon; SLE: systemic lupus erythematosus.
Species Viruses Transcription Factors Chromosome Disease/Function Reference
Human HERV-K5Hs, 5A, 5B Sox2, Oct4, and Nanog chr5q33.3 Neurodegenerative disease [14][15]
HERV-K and HERV-L DUX4 chr17q and chr7p22 FSHD [23]
HERV-K5Hs, and HERV-1 HIF   Kidney cancer [24]
HERV-K5Hs c-Myc chr7p22.1a and chr7p22.1b AT/RT [25]
HERV-K5Hs NF-κB and IRF1   ALS [26]
HERV-K5Hs PR/Estradiol   Breast cancer [27]
HERV-K5Hs and HERV-E Sp1 and Sp3   Skin cancer [6]
HERV-K5Hs TDP-43   ALS [28]
HERV-K5Hs, 5A, 5B p53, p60, and p65   Leukemia, ovarian, and colorectal cancers [4][7]
HERV-K5Hs YY1   Cancers [29][30]
HERV-K NF-AT   HIV associated malignancy [31]
HERV-K MITF-M chr1 Melanoma [32]
HERV-K STAT-1 and IRF1   Inflammatory disease and IFN-γ signaling [33]
HERV-K USF-1   Wound repair regulation [15]
HERV-K Tax   Associated with opportunistic infection [34]
HERV-K Tat   Associated with opportunistic infection [31]
HERV-K18 IFN-α chr1q21.2-1q22 Type-1 diabetes [35]
HERV-K102 IFN- γ   Leishmaniasis [33]
HERV-L HNF-1   Colon cancer [36]
HERV-W c-Myb/HOXA5 chr7q21.2 Tumor progression [37]
HERV-W OCT-1   Cell abnormalities [38]
HERV-W Sp1 and Sp3   Lung fibroblasts [39]
HERV-W GCM-a chr7q21-7q22 Placental formation [40]
HERV-E HIF-2α HIFs, HIF-1α, HIF-2α, and HIF-1β   Kidney cancer [41]
HERV-E NAFT1 chr19p12 SLE [42]
HERV-H Sp1, GC box, and TATA box   Breast cancer [43][44][45][46]
HERV-H LBP9, Oct4, Nanog, and Klf4   Chromosome duplication [47]
HERV-T GATA4, and FOXA2   Endoderm specification [48]
ERV-9 GATA-2, NF-Y, and MZF1   Chromatin remodeling [49]
Double homeobox 4 (DUX4) is another prominent TF that activates HERV-L LTRs in rhabdomyosarcoma cells (muscle cancer cells) [23][50][51][52]. Indeed, ERV transcripts were detected in the skeletal muscles of individuals diagnosed with facioscapulohumeral muscular dystrophy (FSHD) [23][52]. RNA-seq and ChIP assay results suggest that DUX4 overexpression causes the initial manifestation of FSHD [23]. Notably, DUX4 induces HERV-K LTR5Hs on chromosome 7p22 in glioblastoma and myoblastoma cell lines (Table 1), which may result in neurological diseases [23][53].
The resurrection of HERV-K LTRs is alarming for genomic stability and may be associated with the initiation and upregulation of renal cell carcinoma (RCC) [24][54][55][56]. Numerous studies have reported the expression of different HERVs in patients with RCC [57]. In patients with RCC, HERV-K LTR5Hs LTR is located on the long arm of chromosome 6, and HERV-E LTR is significantly expressed in the presence of hypoxia-inducible transcription factor (HIF), which binds to transcriptionally active LTR elements [57]. Thus, evidence suggests that HIF-dependent reactivation of dormant promoters embedded within endogenous retroviral LTRs is a potential contributing factor to dysregulated gene expression in RCC [24].
Previous research on the binding motifs of TFs revealed the presence of microphthalmia-associated transcription factor-M (MITF-M) on HERV-K LTR as well as some other retroviral LTRs [32]. The expression of HERV-K on chromosome 1 was shown to be significantly higher in the presence of MITF-M in melanoma and HEK293 cells [32][58]. Further analysis uncovered that the sequence of MITF-M (MITF-1, MITF-2, and MITF-3), TATA, and Inr is quite conserved (5′CACATG3′) in over a hundred HERV-K LTRs [32]. Mutants of the MITF-1, -2, or -3 motifs at the HERV-K LTR were unable to initiate transcripts in malignant melanoma cell lines (MeWo cells), which express large amounts of endogenous MITF-A and -M [32]. MITF-M binds to the LTR at the 5′ and 3′ ends, activating both HERV-K LTRs [32][58][59]. This suggests that MITF-M alters the expression of neighboring genes in malignant melanoma cells.
HERV-K env RNA expression is upregulated in patients with atypical teratoid rhabdoid tumor (AT/RT) by deletion or mutation of integrase interactor 1 (SMARCB1) [25]. Based on computational assessment using the PROMO software v8.3 of TRANSFAC, c-Myc protein binding sites were identified within the HML-2 LTR5Hs sequences [60]. SMARCB1 is a transcriptional repressor of HIV-1 LTR [61]. The active LTRs in loci 7p22.1a and 7p22.1b are highly expressed in patients with AT/RT as a result of c-Myc binding to the HERV-K LTR (Table 1) [25]. Similar results were found in 293T cells [61], suggesting that SMARCB1 is a repressor and c-Myc is an activator for HERV-K LTR in AT/RT.
HERV-K is actively involved in breast cancer progression in the presence of female sex hormones estradiol and progesterone [27]. Although estradiol and progesterone have other biological functions, they synergistically activate HERV-K through their receptors in T47D human breast cancer cells [27]. Electrophoretic mobility shift assay (EMSA) and co-immunoprecipitation assay showed that the progesterone receptor (isoform B) binds to the progesterone response element within LTR5Hs [27]. Conversely, overexpression of Oct4 significantly (two-fold) enhanced HERV-K10 transcription, and progesterone treatment synergistically activated HERV-K10 LTR in primary mammary epithelial cells [27]. Thus, it can be assumed that HERV-K, which is activated by female sex hormones, drives breast cancer progression [27].
The TF Yin Yang 1 (YY1) is highly conserved from African clawed frogs (Xenopus laevis) to humans [62][63]. It is ubiquitously expressed in pluripotent differentiated cells, mouse teratocarcinoma cells (F9), mouse fibroblasts (NIH3T3), rat embryo fibroblasts, and HeLa cells [64][65]. YY1, together with different cofactors, mediates the activation, repression, or initiation of transcription in ERVs [66]. YY1 binds to a motif within 62nt-83nt of the HERV-K LTR5Hs and acts as an enhancer-binding protein in human teratocarcinoma (GH and Tera2), hepatocarcinoma (HepG2), and HeLa cells [29]. Additionally, YY1 enhancer complexes activate HERV-K LTR5Hs by binding at the 5′ end of the U3 region [29]. In contrast, YY1 induces silencing of exogenous and endogenous retroviruses by recruiting tripartite motif-containing protein 28 (TRIM28) and its complex in mouse embryonic cells [30][67][68][69][70]. Thus, ERV LTR is activated or suppressed depending on the transcriptional activator or repressor that binds to YY1; therefore, it is important to investigate the relationship between YY1-binding cofactors and diseases.
HERV-K is also associated with numerous neural diseases [71]. HERV-K env leads to neuronal injury in the presence of the transactive response DNA-binding protein 43 (TDP-43) [28]. The co-expression of HERV-K RT and TDP-43 proteins has been observed in most neurons, with a significant positive correlation between them [72]. Five different TDP-43 binding sites were found on the HERV-K LTR, which regulate its activation [28]. Human neural cells transfected with TDP-43 showed enhanced HERV-K expression, whereas knockdown of endogenous TDP-43 resulted in decreased HERV-K expression [28]. In addition, the levels of antibody against HERV-K were markedly increased in patients with ALS, multiple sclerosis, and Alzheimer’s disease [73]. Moreover, specific post-translational modifications of TDP-43 may affect HERV-K expression patterns. For example, formation of TDP-43 aggregates alters HERV-K RT expression and cellular localization of viral proteins [26]. Misfolded TDP-43 is aggregated and transmitted in patients with ALS [74]. Interestingly, prion-like proteins (e.g., yeast Sup35 prion NM domain and Tau microtubule-binding domain) are transmitted by ERVs such as HERV-K and HERV-W [75]. Thus, if ERVs form particles and become active in other cells by transmitting TFs listed in Table 1, including TDP-43, they may be involved in diseases such as ALS.
HERV-K LTRs and HERV-E.PTN are TATA-independent promoters regulated by three GC boxes that serve as binding sites for Sp1 and Sp3 [6][76]. Sp1/Sp3 are TFs for TATA-less promoters that are available early after zygote formation [77]. HERV-K LTR activation was reduced by approximately 20% and 50% following knockdown of Sp1 and Sp3, respectively, in human melanoma (Mel-C9) and teratocarcinoma (GH) cell lines [6]. Mutation of the Sp1-binding motif (451–462 nt) in HERV-E.PTN markedly reduced transcriptional activity in choriocarcinoma cells of the fetal placenta (JEG-3, BeWo, and JAR). Since HERV-W and HERV-FRD Env play critical roles in placental development [40], Sp1 and Sp3 may trigger HERV-W transcription in placental cells. However, the active HERV-W LTR has a mutation in the Sp1-binding motif, while the inactive HERV-W LTR has an intact Sp1-binding motif in lung fibroblasts (LC5) (Table 1) [39]. Thus, transcriptional activation by Sp1 and Sp3 is complex, and their regulatory mechanisms may differ depending on other transcription elements and cell lines.

1.2. Viral Infection Activates HERV-K and HERV-W Expression

The HTLV-1 Tax protein, detected in patients with myelopathy or tropical spastic paraparesis (HAM/TSP), is a powerful trans-activator capable of inducing many cellular genes through its activation domains [78]. HTLV-1 Tax trans-activator could activate the LTRs of different HERV families (HERV-W8, HERV-H, HERV-K, and HERV-E) in T cell lines [34]. Indeed, various Tax mutants have been shown to affect LTR activation to different degrees. Moreover, modulation of these LTRs by Tax activated CREB and possibly NF-κB in Jurkat cells, which in turn may positively regulate the transcription of HERV genes or other proximal cellular genes in HTLV-1-infected patients [34].
Several TFs listed in Table 1, such as AP-1, CREB, CEBP (C/EBPα), c-Rel, NF-AT, CEBPβ, NF-κB (p50:p52), Rel-A, p53, YY1, c-Myc, Sp1, Sp3, and signal transducer and activator of transcription 1 (STAT1), potentially interact with HERV-K LTRs. Interestingly, multiple NF-κB sites are present in the HERV-K promoter [79][80]. Luciferase reporter gene and ChIP assay analyses showed that NF-κB mediates the activation of HERV-K via HIV-1 Tat protein [31]. As the HERV-K LTR contains potential NF-AT binding sites, NF-AT activation could additionally contribute to HERV-K Tat-driven expression and might compensate for the absence of NF-κB activity. These reports suggest that both NF-κB and NF-AT activation in response to HIV-1 Tat drives transcription from the HERV-K promoter in HIV-1-infected patients [31]. HIV-1 release and infectivity are reduced by coassembly between HIV-1 Gag and HERV-K Gag in the HERV-K Gag-overexpressing cells [81][82] (Figure 1G). The endogenous retroviruses might be activated by the infection of exogenous retroviruses to protect the host cells from exogenous retroviral threats.
LTR-driven HERV-W transcription is activated by herpes simplex virus type 1 (HSV-1) immediate early protein (IE1) through the cellular TF Oct-1 [38]. In addition, anti-HERV-W antibody level is elevated with anti-Epstein–Barr virus antibody in the patients with autoimmune demyelinating disorders [83]. Two Oct-1-binding motifs are conserved in the HERV-W LTR series [39]. Specifically, few HERV-W LTRs are stimulated in the presence of IE1, which potentially upregulates the expression of other genes [38]. Furthermore, HSV-1 immediate early protein (ICP0) increases HERV-K transcription via the AP-1-binding motif in the LTR [84]. Therefore, the relationship between various HSV-1-associated diseases and HERVs is a topic for future research.
Subsequent research has clarified that HERV-W LTR is also activated by influenza A/WSN/33 infection [85]. Although its underlying mechanism remains to be elucidated, the induction of HERV-W was found to depend on the cell line, because the expression of HERV-W gag and env genes was relatively enhanced in influenza-infected CCF-STTG1 and U937 cells, but not in 293F cells. Notably, interferon beta (IFN-β) level positively correlated with HERV-W expression in the infected cells [85]. This suggests that IFN-induced HERVs expression cannot be disregarded.

1.3. Interferon-α, and γ Trigger HERV-K Expression

Superantigen (SAg) IDDMK1,2 22, associated with type-1 diabetes, is derived from HERV-K18 mapped on chromosome 1q21.2-q22 [86]. IFN-α treatment upregulated the expression of SAg and HERV-K18 in T cells, while a cocktail treatment of IFN-α and IFN-γ markedly increased HERV-K18 expression [35], suggesting that HERV-K18 is induced by IFN-α and this induction can be amplified by IFN-γ priming.
IFN-γ signaling-induced HERV-K102 expression has been demonstrated in various cell lines [33]. Expression of HERV-K genes was higher in patients with cutaneous leishmaniasis, and IFN-γ level is known be elevated in these due to leishmania parasite infection [33][87]. Transposase-accessible chromatin sequencing (ATAC-seq) and ChIP sequencing analyses showed the HERV-K102 expression was upregulated via solo-LTR LTR12F upon treatment with IFN-γ in HeLa cells [33]. IFN regulatory factor 1 (IRF1) and, potentially, STAT1 are conjugally recruited to activate LTR12F located upstream of HERV-K102 [33]. Upon activation of LTR12F along with the enhancer histone H3 dimethylation of lysine 4 (H3K4me2), HERV-K102 activates following IFN-γ signaling [33]. This suggests that HERV-K102 activation is sensitive to IFN-γ and is regulated through IRF1 recruitment followed by LTR12F activation. The notable finding is that HERV-K102 expression is upregulated by utilizing upstream solo-LTR rather than its own LTRs, and that IFN-γ and IRF1 recruitment are the trigger for solo-LTR activation.

2. TFs Associated with LTR Activation of Other HERVs

HERVs are classified according to the type of tRNA that binds to the primer binding site (PBS) located downstream of the 5′LTR. For example, in the case of HERV-K, HERV-K utilizes a lysine (K) tRNA, and in the case of HERV-W, it is tryptophan (W) tRNA [88].

2.1. HERV-E Is Activated by HIFs, Nuclear Factor of Activated T-Cells 1 (NFAT1), and Estrogen Receptor Alpha (ER-α)

HERV-E (CT-RCC-8 and CT-RCC-9), located on the long arm of chromosome 6 (GenBank accession number AL133408), is selectively expressed in most RCCs [89]. Notably, HERV-E Env protein has antigenic properties that immunologically provoke cytotoxic T cells to kill RCC cells both in vitro and in vivo [55][89]. HERV-E provirus was shown to be resurrected in the clear cell subtype of RCC (ccRCC) upon inactivation of the von Hippel–Lindau (VHL) gene, which is a tumor suppressor gene [41]. Furthermore, this activation of HERV-E can be stabilized by HIF-2α but not HIF-1α [41]. Computational analysis showed that the binding motif of HIF-2α is located on the HERV-E LTR, and in vitro investigation found a direct correlation between the expression levels of HIF-2α and HERV-E in ccRCC [41]. Furthermore, ChIP analysis revealed a direct binding association between HIF-2α and HERV-E 5′LTR [41]. Taken together, these findings suggest that of VHL suppression-activated HERV-E, which could be promoted and stabilized by HIF-2α in RCC [41].
Elevated ERV protein levels have also been found in patients with systemic lupus erythematosus (SLE) [90], and autoreactive CD4+ T cells play a principal role in this disease [91]. The TFs NFAT1 and ER-α bind to the HERV-E clone 4-1 LTRs located on chromosome 19p12 [42]. Overexpression of NFAT1, and ER-α activated the HERV-E clone 4-1 5′LTRs in CD4+ T cells of patients with SLE, as revealed by luciferase reporter and the ChIP assay analyses [42]. In contrast, the antisense RNA miR-302d transcribed from the 3′LTR of HERV-E clone 4-1 induces DNA hypomethylation and is associated with SLE [42]. The hypomethylation activity of HERV-E has been confirmed in patients with SLE by COBRA validation [92][93]. Moreover, studies have reported that HERV-E mRNA, but not HERV-K and HERV-W, is increased in CD4+T cells from patients with SLE, suggesting a crucial role for HERV-E in the development of SLE [94].

2.2. HERV-L Is Activated by the Hepatocyte Nuclear Factor (HNF-1)

Solo-LTR (MLT2Bs), a member of the HERV-L family, is a promoter of the human beta-1,3-galactosyltransferase 5 (β3Gal-T5) gene, which is involved in type 1 Lewis antigen synthesis [36]. The ERV-L LTR promoter is most active in the gastrointestinal tract and mammary glands [36]. HNF-1 binds to ERV-L LTR and acts as a TF [36]. Two predicted sites for HNF-1 binding were identified at nucleotide positions 7–21 and 33–46 using the TRANSFAC TF database [36]. HNF-1 is expressed in tissues where the LTR promoter is active, including the intestine, stomach, kidneys, liver, and thymus [95]. LTR-driven β3Gal-T5 is expressed in the mammary glands, small intestine, trachea, colon, thymus, stomach, kidneys, liver, and lungs [36]. Of the two HNF-1-binding sites in the HERV-L LTR, the second site (position 33–46) was more important for the specific activation of the LTR promoter in a colorectal cancer cell line (LoVo). HNF-1, therefore, represents a candidate TF responsible for the tissue-specific activation of the HERV-L LTR promoter in various cancer cells, such as colorectal cancer cells.

2.3. HERV-W Is Activated by Glial Cells Missing-a

Human glial cells missing-a/1 (GCM-a/1) and murine glial cells missing-a (mGCM-a) are placenta-specific TFs required for placental development [96][97]. The HERV-W env syncytin-1, positioned on chr7q21-chr7q22, is regulated by GCM-a in BeWo and JEG3 cells [98]. Binding motif analysis identified two GCM-a-binding sites (25538-25545, 28026-28033) upstream of the HERV-W 5′LTR (GenBank accession no. AC000064; 7q21-7q22). Therefore, GCM-a can easily transactivate syncytin-1 gene, especially in trophoblasts [40]. The close proximity between the GCM-a-binding site and the LTR ensures the formation of an integral syncytiotrophoblast layer in the placenta [40].
Notably, GCM1 expression is activated via the WNT signaling pathway [99], suggesting that GCM1 and WNT signaling upregulate HERV-W expression in placental cells. In contrast, the HERV-W env protein increased the proliferation and viability of immortalized human uroepithelial cells. Results of colony-formation experiments and in vivo tumor xenografts suggest that syncytin-1 overexpression, due to two mutations in the 3′-LTR (T142C and A277G), has oncogenic potential in the urothelial cell carcinoma (UCC) [37]. The T142C mutation favors the binding of TF c-Myb to HERV-W 3′-LTRs and upregulates syncytin-1 overexpression [37]. This suggests that further research on HERV-W is important not only to elucidate the biological evolution due to placentation, but also to explore its relationship with development of cancers, such as UCC.

2.4. HERV-H Is Activated by Sox2, Nanog, and Oct4

HERV-H is present in the human genome as 100 full-length copies and >1000 solo-LTR copies. The solo-LTR of HERV-H was integrated into a gasdermin-like protein (GSDML) located on chromosome 17q21 during hominoid evolution. This solo-LTR drives GSDML–GSDM gene transcription in human gastric and breast cancers [43][44]. The expression and promoter activity of HERV-H LTR depend on the cell type [39]. Moreover, the HERV-H LTR has different TF-binding sites, such as Sp1, GC box, and TATA box [45][46]. RNA-seq revealed a binding association between HERV-H and the TFs Sox2, Nanog, and Oct4. During differentiation of embryonic stem cells (ESC), this binding association was greater for Sox2 than that for Nanog or Oct4 [100]. Ectopic expression of LBP9, Oct4, Nanog, and Klf4 activated HERV-H transcription in human primary fibroblasts, whereas overexpression of Myc or Sox2 failed to activate HERV-H [47]. Disruption of HERV-H transcripts compromises self-renewal, suggesting an important role for HERV-H expression in pluripotency [47]. Interestingly, the HERV-H transcripts (ESRG) play a crucial role in the maintenance of human pluripotency in iPSCs [101]. In summary, further studies on the transcriptional regulation of HERV-H and the function of its transcripts are important for the development of regenerative medicine using iPSCs.

2.5. HERV-S71 (HERV-T) Is Activated by GATA4 and FOXA2

GATA4 and Forkhead box protein A2 (FOXA2) are two distinct TFs that drive the regulatory network of the endoderm [102][103]. Both TFs were upregulated during definitive endoderm (DE) differentiation of hESCs. LTR6B, a DE-specific enhancer of ERVs, contains GATA4- and FOXA2-binding motifs and flanks HERV-S71-int [48], which is classified as HERV-T [104]. GATA4 and FOXA2, which bind to LTR6B, activated neighboring genes located in the vicinity of ~50 kb in DE cells, as determined by ChIP seq. This was supported by the finding that FOXA2 depletion downregulated the expression of LTR6B in DE cells, as shown by ATAC-seq and H2K27ac ChIP-seq analyses [48]. Thus, GATA4 and FOXA2 play a critical role in activating neighboring genes by binding to ERV LTR6B [48].


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