Aberrant hydroxymethylation of <i>ANGPTL4</i> is associated with selective intrauterine growth restriction in monochorionic twin pregnancies

Selective intrauterine growth restriction (sIUGR) is a severe complication in monochorionic (MC) twin pregnancies, and it carries increased risks of poor prognosis. Current data suggest that vascular anastomoses and unequal placental sharing may be the key contributor to discordant foetal growth. While MC twins derive from a single zygote and have almost identical genetic information, the precise mechanisms remain unknown. DNA hydroxymethylation is a newly discovered epigenetic feature associated with gene regulation and modification. Here, we investigate discordant hydroxymethylation patterns between two placental shares of sIUGR and analyse the potential role of aberrant hydroxymethylation of angiopoietin-like 4 (<i>ANGPTL4</i>) in placental dysplasia. Hydroxymethylation DNA immunoprecipitation (hMeDIP)-chip and mRNA sequencing were performed to identify hydroxymethylation-associated genes. Real-time qPCR, western blotting, and immunohistochemistry were used to confirm <i>ANGPTL4</i> expression. The mechanisms regulating <i>ANGPTL4</i> were investigated by cell migration assay, invasion assay, viability assay, and apoptotic ratio assays, western blotting and hMeDIP-qPCR. Decreased <i>ANGPTL4</i> was detected in the smaller placental shares of sIUGR. <i>ANGPTL4</i> knockdown suppressed trophoblast invasiveness and migration, which possibly occurred through hypoxia inducible factor 1α (<i>HIF-1α</i>) and <i>HIF-1</i> signalling pathway. Hypoxia leads to aberrant expression of <i>ANGPTL4</i> and <i>HIF-1α</i>, positively correlated with their aberrant hydroxymethylation levels in promoter regions. Aberrant hydroxymethylation of <i>ANGPTL4</i> may contribute to placental impairment by the <i>HIF-1</i> signalling pathway in smaller placental shares of sIUGR.