De-repression of Transposable Elements by Histone Hyperacetylation Leads to Sterile Inflammation in Preeclampsia

Preeclampsia is a pregnancy-associated hypertension disorder that affects 5–10% of pregnant women each year, resulting in adverse outcomes for both mother and child. Although the pathophysiology of preeclampsia remains somewhat unclear, it is linked to inflammation, senescence, and accelerated ageing phenotypes. Here, we aimed to investigate the altered epigenetic and transcriptomic changes in preeclampsia by performing genome-wide enrichment analysis of histone acetylation at histone H4 lysine 16 (H4K16ac) and H3 lysine 27 (H3K27ac) along with RNA sequencing analysis in preeclamptic and control placentas. We discovered transposable element (TE) families, including long terminal repeats (LTRs), endogenous retroviruses (ERVs), long interspersed nuclear elements (LINE), and short interspersed nuclear elements (SINE), are upregulated in preeclampsia. TEs upregulated in preeclampsia showed higher levels of H4K16ac, suggesting the contribution of this epigenetic modification in the regulation of TE transcription in the preeclamptic placenta. Genes closer to H4K16ac marked and upregulated TEs are expressed at higher levels in preeclampsia, suggesting that these TEs regulate transcription of nearby genes through their enhancer activity. Furthermore, we demonstrate that the upregulation of TEs results in double-stranded RNA (dsRNA) accumulation in trophoblast cells in the preeclamptic placenta. These TE-derived dsRNAs are detected by antiviral nucleic acid sensors, such as retinoic acid-inducible gene I (RIG-I) like receptors (RLRs), resulting in sterile inflammation due to the activation of the antiviral innate immune system. Our findings indicate that the epigenetic de-repression of TEs in the human placenta activates the type-I interferon response, leading to sterile inflammation in the preeclamptic placenta.