Limited evolutionary conservation of imprinting in the human placenta

Abstract

The epigenetic phenomenon of genomic imprinting provides an additional level of gene regulation that is confined to a limited number of genes, frequently, but not exclusively, important for embryonic development. The evolution and maintenance of imprinting has been linked to the balance between the allocation of maternal resources to the developing fetus and the mother's well being. Genes that are imprinted in both the embryo and extraembryonic tissues show extensive conservation between a mouse and a human. Here we examine the human orthologues of mouse genes imprinted only in the placenta, assaying allele-specific expression and epigenetic modifications. The genes from the KCNQ1 domain and the isolated human orthologues of the imprinted genes Gatm and Dcn all are expressed biallelically in the human, from first-trimester trophoblast through to term. This lack of imprinting is independent of promoter CpG methylation and correlates with the absence of the allelic histone modifications dimethylation of lysine-9 residue of H3 (H3K9me2) and trimethylation of lysine-27 residue of H3 (H3K27me3). These specific histone modifications are thought to contribute toward regulation of imprinting in the mouse. Genes from the IGF2R domain show polymorphic concordant expression in the placenta, with imprinting demonstrated in only a minority of samples. Together these findings have important implications for understanding the evolution of mammalian genomic imprinting. Because most human pregnancies are singletons, this absence of competition might explain the comparatively relaxed need in the human for placentalspecific imprinting.histones ͉ methylation ͉ epigenetics

Imprinted gene expression in hybrids: perturbed mechanisms and evolutionary implications

“…For example, at the IGF2-receptor (IGF2R) gene, mono-allelic expression from the maternal allele occurs in a minority of individuals only (Monk et al, 2006;Yotova et al, 2008). Unexpectedly, the maternal DNA methylation imprint at this locus was normally present in all individuals (Vu et al, 2006).…”

“…The regulatory long non-coding RNA produced from the unmethylated allele of the imprinting control region (ICR), however, was expressed in some individuals only. Lack of expression of this long non-coding RNA correlates with biallelic expression ('loss of imprinting') of IGF2R and of close-by placenta-specific genes (Monk et al, 2006). The growth-related PEG1/MEST gene on human chromosome 7q32 is polymorphically imprinted (Huntriss et al, 2013); its isoform-2 in placenta and early embryos is highly variable between conceptuses and this correlates with differential DNA methylation levels at an exonic differentially methylated region (McMinn et al, 2006).…”

Differential expression of imprinted genes in normal and IUGR human placentas

“…The exact number of human imprinted genes is however difficult to determine because monoallelic expression of imprinted genes may occur in one specific isoform, only in specific tissue types, or only at a specific stage of development. 8 Intrauterine growth restriction (IUGR), which accounts for almost 10% of all pregnancies in the US, is associated with major perinatal morbidity and mortality in comparison to their normal size, appropriate for gestational age neonates. 11,12 Although IUGR has multifactorial etiologies, one major cause of IUGR is that of uteroplacental insufficiency; i.e., an imbalance between fetal nutritional or respiratory demands and uteroplacental reserve.…”

Macro lncRNAs

“…In humans, IGF2R shows polymorphic imprinted expression in some fetal tissues but biallelic expression in adult tissues. 42 The human AIRN promoter has been identified, however, a clear correlation between AIRN expression and IGF2R repression has not yet been established. 43 The Kcnq1ot1 macro lncRNA silences the Kcnq1 imprinted gene cluster.…”

“…Six genes: Ascl2, Tspan32, Cd81, Tssc4, Nap1l4 and Osbpl5 only show imprinted expression in placental tissues. 42,44 Recent studies however, challenge the imprinted status of Tssc4, Nap1l4 and Osbpl5, since their high expression in the maternal decidua invalidates their analysis in mouse placenta. 39,45,46 The Nespas macro lncRNA silences the Gnas imprinted gene cluster.…”