Endogenous Retroviral Elements in Human Development and Central Nervous System Embryonal Tumors

Abstract

Human endogenous retroviruses (HERVs), which are critical to normal embryologic development and downregulated during normal maturation, have been implicated in a variety of cancers. Abnormal persistent production of HERVs has been suggested to play a role in oncogenesis and to confer stem cell properties to cells. We recently demonstrated that the most recently incorporated HERV element (HERV-K HML-2) has been associated with the pathogenesis of the embryonal atypical teratoid rhabdoid tumor (AT/RT), shifting our understanding of embryonal tumor development. HML-2 expression is vital for proper human development and its expression is suppressed via methylation or chromatin remodeling as cells differentiate. We previously found that dysfunctional chromatin remodeling due to loss of SMARCB1 expression induces HML-2 envelope (env) expression, impairing cellular differentiation and migration, and facilitating tumor growth in AT/RT. Epigenetic dysregulation in other embryonal tumors with concomitant expression of stem-cell markers may facilitate HML-2 expression. Future studies could utilize HML-2 as potential diagnostic criteria, use its expression as a treatment biomarker, and investigate the efficacy of therapies targeting cells with high HML-2 expression.

Does the interplay between human endogenous retrovirus K and extracellular vesicles contribute to aging?

“…A key epigenetic regulator, the chromatin remodeling SWItch/Sucrose Non-Fermentable (SWI/SNF) complex, plays an important role in the transcriptional activation of stress-response genes that are often activated during aging [ 63 ] . In addition, the expression of endogenous retroviruses is tightly spatially and temporally regulated during development, and they are normally downregulated as cells differentiate and mature [ 11 , 64 ] . Therefore, endogenous retroviral expression may be an excellent treatment target for neurodevelopmental tumors, neurodegenerative diseases, and senescence, and current treatments, e.g., anti-retroviral drugs and ERV targeting short hairpin RNAs (shRNAs), designed to abrogate their expression should potentially be explored [ 10 , 26 , 65 ] .…”

“…AT/RT has a bimodal distribution of disease in both young and older individuals, highlighting the possibility of endogenous retroviral involvement in tumors occurring later in life [62] . A key epigenetic regulator, the chromatin remodeling SWItch/Sucrose Non-Fermentable (SWI/SNF) complex, plays an important role in the transcriptional activation of stress-response genes that are often activated during aging [63] . In addition, the expression of endogenous retroviruses is tightly spatially and temporally regulated during development, and they are normally downregulated as cells differentiate and mature [11,64] .…”

Epigenetic Regulation in Primary CNS Tumors: An Opportunity to Bridge Old and New WHO Classifications

“…Within this large, heterogeneous category of CNS primary tumors, epigenetic profiling represents an additional means of investigating these discrepancies and reconciling them. For example, alterations in the SWI/SNF pathway have been found in gliomagenesis as well as aberrant ERV expression [14,15,17,24,25,33,146,147]. This targeted treatment based upon individual tumor profiling may provide a unique therapeutic opportunity for tumors that have historically been treated by non-specific means, which harbor their own potential for inducing tumorigenesis, such as chemotherapy and radiation [148,149].…”

“…Further, we have recently shown that LOF of SWI/SNF proteins can lead to the activation of endogenous retroviruses (ERVs) such as human endogenous retrovirus K (HERV-K, sub-type HML-2) [10]. Normally, ERV expression is tightly spatially and temporally controlled during development, and its expression is significantly downregulated as cells differentiate and mature; therefore, ERV expression provides an excellent target for tumor treatment [10][11][12][13][14][15][16][17]. Potential mechanisms that allow for aberrant expression of ERVs, such as LOF of the SWI/SNF complex, provide a unique opportunity for a combinatorial approach to the treatment of tumors with few targeted treatment options.…”

Viral proteins and virus-like particles of the LTR5_Hs endogenous retrovirus in human primordial germ cell-like cells

“…Human endogenous retroviruses (HERVs) are remnants of ancient infection by retroviruses, comprising nearly 8% of the human genome (Deniz et al, 2018; Durnaoglu et al, 2021a; Geis and Goff, 2020; Groh and Schotta, 2017; Liu et al, 2014; Mao et al, 2021). Whereas most HERVs are permanently inactivated by accumulated mutations or strongly suppressed by epigenetic machineries, some of the activation-competent copies of HERVs may play critical roles in a wide variety of human diseases, including various malignancies, autoimmune diseases, and neurological disorders (Babaian and Mager, 2016; Doucet-O’Hare et al, 2021). Non-physiological reactivation of HERVs may be caused by malnutrition, exposure to environmental toxicants, or impaired health conditions (Sakurai et al, 2019; Sharif et al, 2013; Shioda et al, 2022).…”