Contribution of Syncytins and Other Endogenous Retroviral Envelopes to Human Placenta Pathologies

Fusion, proliferation, angiogenesis, immune tolerance, and tissue survival are some of the critical functions involved in the physiological and pathological processes of placenta development. Strikingly, some of these properties are shared by envelope glycoproteins of retroviruses. Part of the overall retroviral world, the human retroviral heritage consists of hundred thousands of elements representing a huge amount of genetic material as compared to our 25,000 genes, whereas only a few tenths of retroviral loci still contain envelope genes exhibiting large open reading frames. Some of these envelopes, namely Syncytin-1, Syncytin-2, and ERV-3 Env, were shown to support essential functions in placenta development. First, in order to understand where these envelope genes originate and what are the critical mechanisms involved in transcription regulation and protein basic functions such as recognition of cellular receptor by viral envelopes, we will describe the retroviral life cycle and how repeated infections during species evolution led to the formation of retroviral families. We will emphasize how many envelope genes remain in our genome and in which organs they were found to be expressed. Second, Syncytin-1 will be used as a model to decipher essentially in placental context (i) the detailed modalities of transcriptional control including repressive histone marks and CpG methylation epigenetic mechanisms, involvement of tissue-specific transcription factors, and control of mRNA splicing, as well as (ii) the multiple steps required for protein maturation finally leading to a functional trimeric glycosylated protein. The extraordinary versatility of Syncytin-1 will permit to demonstrate that such proteins are likely involved in physiological processes not only in placenta but also in other organs, based on evidence of fusion/differentiation, immunomodulation, apoptosis, and proliferation properties. Third, we will describe extensively the altered behavior of the various levels of transcriptional control or of protein functions/localization/maturation displayed by Syncytins and other endogenous retroviral envelopes. We will exemplify how such altered states may contribute to human placenta pathologies, including Down syndrome, preeclampsia/hemolysis, elevated liver enzymes, and low platelets syndrome/intrauterine growth restriction, and gestational trophoblastic diseases including mole and choriocarcinoma. Similar deregulations will be respectively mentioned on this target of fetal invasion that is the endometrium, the reproductive organs that are the testis and the ovary, and in the breast nourisher of the newborn child. All these observations draw outlines of the symbiotic and conflicting mechanisms at work where the retrovirus world and the human world have converged.