Placenta-specific INSL4 expression is mediated by a human endogenous retrovirus element.
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.
Bièche
Ivan
I
Laboratoire de Génétique Moléculaire, Faculté des Sciences Pharmaceutiques et Biologiques, Univeristé René Descartes, Paris, France.
Laurent
Anne
A
Laurendeau
Ingrid
I
Duret
Laurent
L
Giovangrandi
Yves
Y
Frendo
Jean-Louis
JL
Olivi
Martine
M
Fausser
Jean-Luc
JL
Evain-Brion
Danièle
D
Vidaud
Michel
M
D024506:5' Flanking Region; D017398:Alternative Splicing; D002454:Cell Differentiation; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics; D020077:Endogenous Retroviruses / Q000235:genetics / Q000502:physiology*; D019143:Evolution, Molecular; D015870:Gene Expression; D015894:Genome, Human; D006801:Humans; D007328:Insulin / Q000031:analogs & derivatives* / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D010920:Placenta / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012065:Relaxin / Q000235:genetics; D020079:Terminal Repeat Sequences; D014327:Trophoblasts / Q000166:cytology
C101126:INSL4 protein, human; C512663:INSL6 protein, human; D007328:Insulin; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; C095067:RLN1 protein, human; C095068:RLN2 protein, human; D012333:RNA, Messenger; D012065:Relaxin