Placenta-Specific INSL4 Expression Is Mediated by a Human Endogenous Retrovirus Element1

Abstract

The human insulin-family genes regulate cell growth, metabolism, and tissue-specific functions. Among these different members, only INSL4 gene shows a predominant placenta-specific expression. Here, we show that the human INSL4 gene is tightly clustered with three other members of the human insulin superfamily (RLN1, RLN2, and INSL6) within a 176-kilobase genomic segment on chromosome region 9p23.3-p24.1. We also report evidence that INSL4 is probably the only insulin-like growth factor gene to be primate-specific. We identified an unexpected human endogenous retrovirus (HERV) element inserted into the human INSL4 promoter with a sequence similar to that of env gene, flanked by two long terminal repeats(LTRs). The emergence of INSL4 gene and genomic insertion of HERV appear to have occurred after the divergence of New World and Old World monkeys ( approximately 45 million years ago). Transient transfection experiments showed that the placenta-specific expression of INSL4 is mediated by the 3' LTR of the HERV element, and that the latter may have a major role in INSL4 up-regulation during human cytotrophoblast differentiation into syncytiotrophoblast. Finally, we identified an INSL4 alternatively spliced mRNA species that encodes putative novel INSL4-like peptides. These data support the view that ancient retroviral infection may have been a major event in primate evolution, especially in the functional evolution of the human placenta.

Evolution of the Relaxin/Insulin-like Gene Family in Placental Mammals: Implications for Its Early Evolution

“…In all cases the INSL4 clade is embedded within the RLN1 clade with strong support (Figs. 2, 3), suggesting that this gene arose from an RLN, and not from an INSL ancestor (Bieche et al 2003;Olinski et al 2006b;Wilkinson et al 2005), thus, this phylogeny suggests that the INSL4 gene derives from the duplication of an RLNlike gene that predates the radiation of Euarchontoglires (Fig. 3), and that the gene was secondarily lost in all Euarchontoglires other than catarrhine primates.…”

“…Within mammals, for example, apes posses an additional RLN gene, RLN2, with no clear ortholog in any other vertebrate group, and a similar pattern can be observed for the INSL4 gene, which is only found in catarrhine primates, the group that includes apes and Old World monkeys (Bieche et al 2003;Park et al 2008a, b). Given that the data at hand suggests that the RLN2 and INSL4 genes derive from lineage-specific tandem duplications, we would expect them to nest within the corresponding primate clade in the corresponding phylogenies: the RLN2 clade should nest within apes sequences, and the INLS4 should nest within catarrhine sequences.…”

“…4), in agreement with previous studies. Similarly, it is generally thought that the duplication that gave rise to INSL4 is an evolutionary innovation specific to the catarrhine lineage (Bieche et al 2003). According to this scenario, INSL4 would be expected to be sister to the RLN1/RLN2 clade of human and chimp, to the exclusion of the marmoset RLN1 gene.…”

“…For example, most mammals posses five relatively old paralogs of this family in their genomes: INSL5, RLN1, INSL6, RLN3, and INSL3 (Park et al 2008a, b), while primates have two additional, younger genes (INSL4 and RNL2) that are not present in any other placental lineages (Bieche et al 2003). These genes derive from more recent tandem duplications (Fig.…”

When Competing Viruses Unify: Evolution, Conservation, and Plasticity of Genetic Identities

“…This means that 3.3 gB of human DNA (current size of our genome) was once retrovirus during our evolution. But such LTRs are highly involved in the emergence of new regulatory networks, such as the origin of the placenta (Bièche et al 2003;Chuong et al 2013;Emera and Wagner 2012;Harris 1998;Nakagawa et al 2013) (re-regulating 1500 genes) Lynch et al 2011Lynch et al , 2012 or in the African primates where alteration of 320,000 LTR p53 binding sites occurred onto the p53 cell cycle control network (Wang et al 2007). These primate p53 network changes also relate to (co-operate with) changes in brain specific microRNAs (Le et al 2009), alterations to DNA methylation involved in controlling SINE-derived RNA transcription (Leonova et al 2013), as well as Alu-derived transcription (Zemojtel et al 2009 In proposing the qs-c concept, it was argued that agent diversity (not errors) was essential for the capacity of a collective of RNA agents to function co-operatively (Villarreal and Witzany 2013b).…”