Expression of the Human Endogenous Retrovirus (HERV) Group HML-2/HERV-K Does Not Depend on Canonical Promoter Elements but Is Regulated by Transcription Factors Sp1 and Sp3

Abstract

After fixation in the human genome, human endogenous retroviruses (HERVs) are bona fide cellular genes despite their exogenous origin. To be able to spread within the germ line and the early embryo, the ancient retroviral promoters must have adapted to the requirements for expression in these cell types. We describe that in contrast to the case for current exogenous retroviruses, which replicate in specific somatic cells, the long terminal repeat (LTR) of the human endogenous retrovirus HERV-K acts as a TATA-and initiator elementindependent promoter with a variable transcription start site. We present evidence that the HERV-K LTR is regulated by the transcription factors Sp1 and Sp3. Mutating specific GC boxes, which are binding sites for Sp proteins, and knocking down Sp1 and Sp3 by use of small interfering RNA (siRNA) significantly reduced the promoter activity. Binding of Sp1 and Sp3 to the promoter region was confirmed using electrophoretic mobility shift assays (EMSAs) and chromatin immunoprecipitation (ChIP). Our data explain why certain HERV-K proviruses have lost promoter competence. Since vertebrate promoters lacking canonical core promoter elements are common but poorly studied, understanding the HERV-K promoter not only will provide insight into the regulation of endogenous retroviruses but also can serve as a paradigm for understanding the regulation of this class of cellular genes.Human endogenous retroviruses (HERVs) bear witness that during primate/human evolution exogenous retroviruses have repetitively infected and colonized the germ lines of their respective hosts. HERV sequences constitute approximately 8% of the human genome. However, all present-day proviral loci in the human lineage are rendered noninfectious by mutations and deletions, probably through genetic drift and-given the mutagenic potential of retroviruses-selection for replicationincompetent proviruses. In addition, detailed in silico analyses showed that several HERV proviruses are already inactivated during the primary infection cycle by an APOBEC3G cytosine deaminase, an antiretroviral gene which leaves specific mutation marks within the proviral DNA (17, 33).

Endogenous Retroviruses as Targets for Antitumor Immunity in Renal Cell Cancer and Other Tumors

“…Early studies have suggested that expression of ubiquitous transcription factors such as Sp1, Myb, and YY1 proteins can stimulate transcription of HERVs from hypomethylated LTRs that contain essential binding sites (23–25). Recent data corroborated these observations by providing evidence that the HERV-K promoter activity is dependent on Sp1 and Sp3 transcription factors (26). Using chromatin immunoprecipitation (ChIP) and RNA interference assays, the binding of transcription factors Sp1 and Sp3 to the examined LTR promoter region of HERV-K was shown.…”

Molecular functions of human endogenous retroviruses in health and disease

“…Such a mode of proviral DNA transcription is a basis of the HERV life cycle that provides the possibility of template jumps during proviral RNA reverse transcription. Further studies confirmed the prevailing activity of a non-canonical HERV-K/ HML-2 (ERVK) LTR promoter and showed it is regulated by Sp1 and Sp3 transcription factors via a TATA boxindependent transcription initiation mechanism [229]. A shift of the transcriptional start site can be explained by the initial adaptation to the human genomic context, which can be an early step in the complex process of the HERV sequence domestication and reshaping by the host genome.…”

Human Endogenous Retroviruses-K (HML-2) Expression Is Correlated with Prognosis and Progress of Hepatocellular Carcinoma

“…Fuchs et al reported that the HERV-K transcription is mediated by the transcription factors Sp1 and Sp3 which are upregulated during oxidative stress and cause the gene regulation controlling multiple cellular process, like DNA damage, chromatin remodeling and proliferation, differentiation, and apoptosis of cell [35]. The long terminal repeat (LTR) of HERV-K plays a role of a TATA- and initiator element-independent promoter which has a variable transcription start site and contains four G-rich stretches playing a role of nucleosome free binding regions for Sp1 and Sp3 [35]. The increased expression of HERV-K is related to malignancies, especially hormone-associated cancers.…”