Transcriptional Regulation of Endogenous Retroviruses and Their Misregulation in Human Diseases

Abstract

Endogenous retroviruses (ERVs), deriving from exogenous retroviral infections of germ line cells occurred millions of years ago, represent ~8% of human genome. Most ERVs are highly inactivated because of the accumulation of mutations, insertions, deletions, and/or truncations. However, it is becoming increasingly apparent that ERVs influence host biology through genetic and epigenetic mechanisms under particular physiological and pathological conditions, which provide both beneficial and deleterious effects for the host. For instance, certain ERVs expression is essential for human embryonic development. Whereas abnormal activation of ERVs was found to be involved in numbers of human diseases, such as cancer and neurodegenerative diseases. Therefore, understanding the mechanisms of regulation of ERVs would provide insights into the role of ERVs in health and diseases. Here, we provide an overview of mechanisms of transcriptional regulation of ERVs and their dysregulation in human diseases.

Human endogenous retroviruses and the inflammatory response: A vicious circle associated with health and illness

“…Hence, whilst it was shown that the RNA levels of HERV-K (HML-2) and HERV-W families, in peripheral blood mononuclear cells (PBMC), can gradually increase from young to older adult individuals, it is noteworthy that due to the fact that modulation in HERV expression is under strict control, including the epigenetic aspects, such as DNA methylation, HERV expression levels between young and old individuals cannot be strikingly different. Importantly, infection by exogenous viruses, especially those whose present chronic/latent infection such as Hepatitis C virus (HCV), Herpes simplex virus type 1 (HSV-1), Human T-cell Lymphotropic Virus type 1 (HTLV-1), HIV, Esptein Barr virus (EBV), Kaposi's Sarcoma-associated herpesvirus (KSHV), cytomegalovirus (CMV), may interfere with many of these silencing strategies and play a key role as epigenetic factors that may contributes to the HERVs activation throughout the individuals lifetime (84)(85)(86)(87)(88)(89)(90).…”

Ancient dormant virus remnant ERVW-1 drives ferroptosis via degradation of GPX4 and SLC3A2 in schizophrenia

“…Ferroptosis is a form of cell death driven by iron-dependent lipid peroxidation, representing a new type of programmed cell death distinct from apoptosis, cell necrosis, and autophagy ( Dixon et al., 2012 ). It involves the consumption of unsaturated fatty acids within the plasma membrane and the accumulation of iron-induced lipid reactive oxygen species, leading to oxidative stress response in cells and causing fatal damage to proteins, nucleic acids, and lipids, ultimately resulting in cell death ( Zhang et al., 2022 ). Three main factors are involved in cell death through ferroptosis: the increase of intracellular free iron, the depletion of redox glutathione/GPX4/system Xc-axis, and the oxidation of membrane polyunsaturated fatty acids (PUFAs) ( Jiang et al., 2021 ).…”

Transcriptional Regulation and Its Misregulation in Human Diseases

“…In this Special Issue, a total of 18 excellent and interesting papers [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20], consisting of 13 original research studies [3][4][5][6][10][11][12][14][15][16][18][19][20], as well as five reviews, are published [7][8][9]13,17]. They cover many subjects of transcriptional regulation, including studies on cis-regulatory elements, transcription factors (TF), chromatin regulators, and ncRNAs.…”

“…A class of these elements is represented by the endogenous retroviruses (ERVs), which represent about 8% of the sequences present in the human genome. An interesting overview of this Special Issue [13] describes the mechanisms underlying their transcriptional regulation. During the evolution of the human genome, the accumulation of mutations, insertions, deletions, and/or truncations has rendered these elements inactive.…”

“…During the evolution of the human genome, the accumulation of mutations, insertions, deletions, and/or truncations has rendered these elements inactive. However, it is increasingly evident that, under the influence of genetic and epigenetic mechanisms, they can be involved in some physiological and pathological conditions; examples are their function in embryonic development, or, even more importantly, their reactivation in the development of human diseases, such as cancer and neurodegenerative disorders [13]. Besides, a remarkable paper [14] shows that transcriptional alterations observed in X-linked dystonia-parkinsonism (XDP) are caused by the insertion of a SINE-VNTR-Alu (SVA) retrotransposon in an intron of the TAF1 (TATA-Box Binding Protein Associated Factor 1) gene, encoding for the largest subunit of TFIID; as an interesting effect, increased levels of the TAF1 intron retention transcript TAF1-32i can be found in XDP cells, as compared to healthy controls.…”