Susceptibility allele-specific loss of miR-1324-mediated silencing of the INO80B chromatin-assembly complex gene in pre-eclampsia

Abstract

In humans, the elucidation of the genetics underlying multifactorial diseases such as pre-eclampsia remains complex. Given the current day availability of genome-wide linkage- and expression data pools, we applied pathway-guided genome-wide meta-analysis guided by the premise that the functional network underlying these multifactorial syndromes is under selective genetic pressure. This approach drastically reduced the genomic region of interest, i.e. 2p13 linked with pre-eclampsia in Icelandic families, from 8 679 641 bp (region with linkage) to 45 264 bp (coding exons of prioritized genes) (0.83%). Mutation screening of the candidate genes (n = 13) rapidly reduced the minimal critical region and showed the INO80B gene, encoding a novel winged helix domain (pfam14465) and part of the chromatin-remodeling complex, to be linked to pre-eclampsia. The functional defect in placental cells involved a susceptibility allele-dependent loss-of-gene silencing due to increased INO80B RNA stability as a consequence of differential binding of miR-1324 to the susceptibility allele of rs34174194. This risk allele is located at position 1 in an absolutely conserved 7-mer (UUGUCUG) in the 3-UTR of INO80B immediately downstream of a variant Pumillio Recognition Element (UGUANAAG). These data support that pre-eclampsia genes affect a conserved fundamental mechanism that evolved as a consequence of hemochorial placentation. Functionally, this involves founder-dependent, placentally expressed paralogous genes that regulate an essential trophoblast differentiation pathway but act at different entry points.

Noncoding RNA-regulated gain-of-function of STOX2 in Finnish pre-eclamptic families

“…This has been confirmed experimentally; placental overexpression of Stox1 in transgenic mice caused pre-eclampsia with all features of the human disease7. The STOX2 paralog, INO80B , located between TET3-HK2 in the 2p13 region contains a novel winged helix domain and has been identified as the pre-eclampsia susceptibility gene in Icelandic families6.…”

“…For pre-eclampsia (new onset hypertension with proteinuria during pregnancy), the existence of multiple susceptibility loci (4q34, 2p13, 9p13, 2p25, 10q22, 12q23) in different founder populations (Australia, Iceland, Norway, Finland, Netherlands) is known for decades, but with limited success in the identification of the genes involved123456.…”

“…We postulated that the synteny of the chromosomal regions on 10q22, 2p13 and 4q24-35 with genome wide linkage to pre-eclampsia indicates an evolutionary fundamental mechanism in mammals subject to conserved genetic pressure that evolved as a consequence of hemochorial placentation456. Genetically, this is reflected by different founder effects (Iceland, Netherlands, Australia, Finland) in syntenic chromosomal regions on different chromosomes (2p13, 10q22, 4q24-35) containing paralogous genes ( STOX1, INO80B ) causing the same disease (pre-eclampsia)123456.…”

“…Genetically, this is reflected by different founder effects (Iceland, Netherlands, Australia, Finland) in syntenic chromosomal regions on different chromosomes (2p13, 10q22, 4q24-35) containing paralogous genes ( STOX1, INO80B ) causing the same disease (pre-eclampsia)123456. Functionally, these regions harbor fetally inherited, placentally expressed susceptibility genes for pre-eclampsia that -when defective- cause trophoblast dysfunction in early pregnancy by disrupting a common pathway essential for placentation15.…”

“…Functionally, these regions harbor fetally inherited, placentally expressed susceptibility genes for pre-eclampsia that -when defective- cause trophoblast dysfunction in early pregnancy by disrupting a common pathway essential for placentation15. This pathway involves the transition from proliferative, non-invasive extravillous trophoblast cells to differentiated invasive cells and is central in the establishment of a connection between the maternal and fetal circulations during the first trimester6. When defective, a cascade of events follows that ultimately -months after the initial event- leads to maternal symptoms (Supplementary File 1).…”