Intra-uterine growth restriction (IUGR) is defined by a restriction of fetal growth during gestation. It is a prevalent significant public health problem that jeopardizes neonatal health but also that can have deleterious consequences later in adult life.
Cullins constitute a family of seven
proteins involved in cell scaffold and in selective proteolysis via the
ubiquitin-
proteasome system. Most
Cullins are critical for early embryonic development and mutations in some
Cullin genes have been identified in human syndromes including growth retardation. Our work hypothesis is that
Cullins, particularly CUL4B and CUL7, are involved in
placental diseases and especially in IUGR. Thus, expression of
Cullins and their cofactors was analyzed in normal and pathological placentas. We show that they present a constant significant over-expression in IUGR placentas, whose extent is dependent on the position of the interrogated fragment along the cDNAs, suggesting the existence of different
isoforms of the genes. Particularly, the CUL7 gene is up-regulated up to 10 times in IUGR and 15 times in
preeclampsia associated with IUGR. The expression of cofactors of
Cullins participating to functional complexes has also been evaluated and showed a similar significant increase in IUGR. Promoters of
Cullin genes appeared to be under the control of the
SP1 transcription factor. Finally, methylation levels of the CUL7 promoter in placental tissues are modulated according to the pathological conditions, with a significant hypomethylation in IUGR. These results concur to pinpoint the
Cullin family as a new set of markers of IUGR.