Transcriptional Regulation of Endogenous Retroviruses and Their Misregulation in Human Diseases
Abstract
:1. Introduction
2. Silencing and Transcriptional Regulation of ERVs
2.1. KRAB-ZFPs/TRIM28 Pathway Is a Master Regulator for ERVs Silencing
2.2. Chromatin Remodeler and Histone Chaperone Maintain ERVs Silencing through KRAB-ZFPs/TRIM28 Pathway
2.3. Sumoylation of TRIM28 Contributes to ERVs Silencing
2.4. DNA Methylation in ERVs Silencing
2.5. RNA-Mediated Regulation of ERVs
2.6. Exogenous Viruses Are Associated with ERVs Activation
2.7. Additional Factors in ERVs Transcriptional Regulation
3. Transcriptional Dysregulation of ERVs in Human Diseases
3.1. HERVs in Cancer
3.2. HERVs in Aging and Neurodegenerative Diseases
4. Conclusions and Perspective
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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ERVs Classes | Exogenous Counterpart | Representative ERVs |
---|---|---|
Class I | Gammaretrovirus Epsilonretrovirus | FeLV, GALV, KoRV, McERV, MDEV, MuERV-C, MuRRS, MuRVY, MuLV, GLN, VL30, PERV, HERV-E, F, H, I, P, R, T, W, HERV-FRD |
Class II | Alpharetrovirus Betaretrovirus Deltaretrovirus Lentivirus | ALV, IAP, MMTV, MPMV, MusD/ETn, MINERVa, RELIK, HERV-K (HML-1, 2, 3, 4, 5, 6, 7, 8, 9, 10) |
Class III | Spumaretrovirus | MuERV-L, HERV-L |
HERVs | HERVs Products/Activities | Oncogenic Mechanisms |
---|---|---|
HERV-K (HML-2) | ENV protein | ENV induces EMT and activates ERK pathway in breast cancer [105]. ENV mediates intercellular fusion in melanoma [106]. ENV maintains CD133+ melanoma cells with stemness features [107]. ENV promotes pancreatic cancer proliferation, tumorigenesis, and metastasis by activating RAS/MEK/ERK and JNK/c-Jun signaling pathways [108]. |
Rec protein | Rec activates c-MYC by overcoming the transcriptional repression of testicular zinc-finger protein (TZFP) for c-MYC promoter [109]. Rec relieves the repression of androgen receptor (AR) activity by forming a trimeric complex with TZFP and AR [109], or binds to the human small glutamine-rich tetratricopeptide repeat protein (hSGT) [110]. | |
Np9 protein | Np9 interacts with ligand of Numb protein X, affecting tumorigenesis through the LNX/Numb/Notch pathway [111]. Np9 as a critical molecular switch of multiple signaling pathways in leukemia [112]. Rec and Np9 derepressed c-MYC through the inhibition of promyelocytic leukemia zinc-finger protein (PLZF) [113]. | |
HERV-H | lncRNA | UCA1 enhances proliferation, motility, invasion, and drug resistance of bladder cancer [114]. linc-ROR contributes to progression, metastasis, or chemoresistance in breast cancer [115], pancreatic cancer [116], and hepatocellular carcinoma [117]. |
cis-regulatory element | LTR acts as alternative promoter for GSDML in cervical cancer [118,119]. | |
HERV-E | cis-regulatory element | Modulating PLA2G4A transcription in urothelial cancer [120]. |
syncytin-1/ERVW-1 | ENV protein | Syncytin-1 mediates cancer–endothelial cell fusions in breast cancer [121]. |
ERV-9 | lncRNA | PRLH1 plays an important role in the formation of RNA–protein complex that promotes the HR-mediated DSB repair [122]. |
MaLR | cis-regulatory element | LTR acts as alternative promoter for CSF1R in Hodgkin’s lymphoma [123]. |
MER52A | lncRNA | lncMER52A promotes invasion and metastasis of hepatocellular carcinoma cells by stabilizing p120-catenin [124]. |
MER48 | lncRNA/cis-regulatory element | lncRNA EVADR is associated with adenocarcinomas, and a MER48 ERV element acts as an active promoter for its specific activation [125]. |
Multiple HERVs | dsRNA | dsRNAs derived from the bi-directional transcription of HERVs induce an immunosuppressive tumor microenvironment [91,126]. |
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Zhang, Q.; Pan, J.; Cong, Y.; Mao, J. Transcriptional Regulation of Endogenous Retroviruses and Their Misregulation in Human Diseases. Int. J. Mol. Sci. 2022, 23, 10112. https://doi.org/10.3390/ijms231710112
Zhang Q, Pan J, Cong Y, Mao J. Transcriptional Regulation of Endogenous Retroviruses and Their Misregulation in Human Diseases. International Journal of Molecular Sciences. 2022; 23(17):10112. https://doi.org/10.3390/ijms231710112
Chicago/Turabian StyleZhang, Qian, Juan Pan, Yusheng Cong, and Jian Mao. 2022. "Transcriptional Regulation of Endogenous Retroviruses and Their Misregulation in Human Diseases" International Journal of Molecular Sciences 23, no. 17: 10112. https://doi.org/10.3390/ijms231710112