Template Activating Factor-I α Regulates Retroviral Silencing during Reprogramming.

Reprogramming somatic cells to induced pluripotent stem cells (iPSCs) is accompanied by dramatic changes in epigenetic programs, including silencing of endogenous and exogenous retroviruses. Here, we utilized replication-defective and persistent Sendai virus (SeVdp)-based vectors to monitor retroviral silencing during reprogramming. We observed that retroviral silencing occurred at an early reprogramming stage without a requirement for KLF4 or the YY1-binding site in the retroviral genome. Insertional chromatin immunoprecipitation (iChIP) enabled us to isolate factors assembled on the silenced provirus, including components of inhibitor of histone acetyltransferase (INHAT), which includes the SET/TAF-I oncoprotein. Knockdown of SET/TAF-I in mouse embryonic fibroblasts (MEFs) diminished retroviral silencing during reprogramming, and overexpression of template activating factor-I α (TAF-Iα), a SET/TAF-I isoform predominant in embryonic stem cells (ESCs), reinforced retroviral silencing by an SeVdp-based vector that is otherwise defective in retroviral silencing. Our results indicate an important role for TAF-Iα in retroviral silencing during reprogramming.

Effects of UVA1 Phototherapy on Expression of Human Endogenous Retroviral Sequence (HERV)-K10 gag in Morphea: A Preliminary Study.

BACKGROUND Morphea, also known as localized scleroderma, is a rare autoimmune connective tissue disease characterized by skin fibrosis. UVA1 phototherapy is an important asset in the reduction of clinical manifestations in morphea. There are studies claiming that UV light modulates the expression of some human endogenous retroviral sequences. The aim of this study was to determine if the expression of HERV-K10 gag element is lowered by UVA1 phototherapy in morphea, a disease in which such irradiation has a soothing effect. MATERIAL AND METHODS The expression levels of the HERV-K10 gag were assessed by real-time PCR (polymerase chain reaction) in peripheral blood mononuclear cells (PBMC) and skin-punch biopsies of healthy volunteers and 9 morphea patients before and after phototherapy. Additionally, correlations between the HERV-K10 gag expression and age, disease duration, the Localized Scleroderma Skin Severity Index (LoSSI), and antinuclear antibody (ANA) titers were assessed. RESULTS In PBMC, HERV-K10 gag mRNA was significantly elevated after UVA1 phototherapy compared to healthy controls. Most of the patients responded with an increased expression level of this sequence. However, we found no statistical evidence at this point that phototherapy indeed has an effect on the HERV-K10 gag expression (there were no statistical differences in PBMC of morphea patients before and after phototherapy). Similarly, there was no statistically relevant effect of the UVA1 on the expression of HERV-K10 gag in skin. CONCLUSIONS At this point, the effect of UVA1 phototherapy on the expression of HERV-K10 gag cannot be statistically confirmed.

A new paradigm about HERV-K102 particle production and blocked release to explain cortisol mediated immunosenescence and age-associated risk of chronic disease.

The majority of chronic diseases in the aging adult are thought to relate to immune aging characterized by dominant immunosuppression and paradoxically, concomitant inflammation. This is known collectively as immunosenescence. The main change thought to be controlling immune aging is the age-related decline in dehydroepiandrosterone (DHEA) and corresponding increase in cortisol; the net effect which decreases the DHEA/cortisol ratio. Exactly how this translates to immunosuppression and concomitant inflammation remains unclear. Recently a new component of the human innate immune system has been discovered. Human endogenous retrovirus K102 (HERV-K102) is a replication-competent foamy retrovirus unique to humans which has been implicated in chronic diseases. Accumulating evidence suggests that HERV-K102 may defend the host against viral infections, as well as against breast and other cancers. Particles are produced in activated monocytes and released into vacuoles but do not bud through the cell surface. This renders macrophages foamy, while the release of particles is only through cell lysis. New evidence presented here suggests DHEA but not DHEA-S may specifically bind and inactivate alpha-fetoprotein (AFP). AFP is a well-established immunosuppressive factor which importantly, also blocks cell lysis induction in macrophages through the 67 kilodalton (kD) AFP receptor (AFPr). Here, it is proposed that a decreased DHEA/cortisol ratio may favor the accumulation of foamy macrophages reflecting the cortisol induction of HERV-K102 particle production concomitant with the blocked release of particles by secreted AFP. This is a new paradigm to explain how cortisol-mediated immunosenescence can result in the persistence of foamy macrophages, and how this relates to risk of chronic disease.

Expression of endogenous retroviruses is negatively regulated by the pluripotency marker Rex1/Zfp42.

Rex1/Zfp42 is a Yy1-related zinc-finger protein whose expression is frequently used to identify pluripotent stem cells. We show that depletion of Rex1 levels notably affected self-renewal of mouse embryonic stem (ES) cells in clonal assays, in the absence of evident differences in expression of marker genes for pluripotency or differentiation. By contrast, marked differences in expression of several endogenous retroviral elements (ERVs) were evident upon Rex1 depletion. We demonstrate association of REX1 to specific elements in chromatin-immunoprecipitation assays, most strongly to muERV-L and to a lower extent to IAP and musD elements. Rex1 regulates muERV-L expression in vivo, as we show altered levels upon transient gain-and-loss of Rex1 function in pre-implantation embryos. We also find REX1 can associate with the lysine-demethylase LSD1/KDM1A, suggesting they act in concert. Similar to REX1 binding to retrotransposable elements (REs) in ES cells, we also detected binding of the REX1 related proteins YY1 and YY2 to REs, although the binding preferences of the two proteins were slightly different. Altogether, we show that Rex1 regulates ERV expression in mouse ES cells and during pre-implantation development and suggest that Rex1 and its relatives have evolved as regulators of endogenous retroviral transcription.