Effects of histone H4 hyperacetylation on inhibiting MMP2 and MMP9 in human amniotic epithelial cells and in premature rupture of fetal membranes

Abstract

Histone modification is closely associated with several diseases. The aim of the current study was to investigate the associations among histone acetylation, matrix metalloproteinases (MMPs) and premature rupture of membranes (PROM) during pregnancy. A total of 180 puerperants were divided into three groups: i) Preterm-PROM (PPROM), ii) term-PROM (TPROM) and iii) full-term labor (FTL). Enzyme-linked immunosorbent assay (ELISA) kits and western blotting were used to determine the protein concentrations of MMP2, MMP9, histone deacetylase (HDAC)1, HDAC2 and HDAC6, and the protein levels of histone H4 lysine (H4K)5 and H4K8 acetylation, respectively, in three types of fetal membranes. Additionally, human amniotic epithelial cells were used to determine the effects of the HDAC inhibitors droxinostat and chidamide on cell viability, histone acetylation and the levels of MMP2, MMP9, HDAC1, HDAC2 and HDAC6 in vitro, using the Cell Counting Kit-8 assay, western blotting and ELISA, respectively. Furthermore, the effects of droxinostat and chidamide on the invasion and migration abilities of human amniotic epithelial cells were investigated using transwell assays. In fetal membranes, the activities of MMP2 and MMP9 increased in PPROM, but decreased in TPROM. Further, the expression of HDAC1 was decreased and histone hyperacetylation was increased in both PPROM and TRPOM. In vitro experiments revealed that 5 µM droxinostat and 0.5 µM chidamide selectively decreased the level of HDAC and induced acetylation of H4K5 and H4K8. Additionally, the aforementioned HDAC inhibitors reduced human amniotic epithelial cell viability, invasion and migration, and decreased the expression levels of MMP2 and MMP9. The current study revealed a high expression level of MMP2 and MMP9 in PPROM compared with TPROM and FL tissue, which was in accordance with previously published studies. Furthermore, the in vitro tests performed in the current study revealed the effect of histone H4 hyperacetylation on inhibiting MMP2 and MMP9 levels in vitro was similar to that observed in TPROM. The results obtained in the current study may be used as a theoretical guide for clinical treatment of premature rupture of membranes.

Histone acetylation dynamics in repair of DNA double-strand breaks

“…The acetylation modifications at the N-terminus of the histones are most commonly studied as they are highly accessible at the tails and mediate binding of reader chromatin proteins (Kouzarides, 2007;Soria et al, 2012). Five reversible acetylable lysines are present at the N-terminus of histone H3 namely, 9, 14, 18, 23, and 27, whereas four acetylable lysines are present at positions 5, 8, 12, and 16 at the N-terminus of Histone H4 (North and Verdin, 2004;Wang et al, 2007;Ma and Schultz, 2008;Hulin et al, 2016;Khilji et al, 2021;Song et al, 2021;Wu et al, 2022). Interestingly, covalent modifications also occur within the globular domain of histones, especially at positions that are in close contact with the nucleosomal DNA wrapped around each octamer.…”

The Importance of Tissue Doppler Imaging and M‐Mode Ultrasonography in Fetuses With Preterm Premature Rupture of Membranes

“…oxidative stress are some of the theories that may be associated factors. [2][3][4] Among the other causes of preterm birth, pregnancies with PPROM have the most adverse perinatal outcome. Complications are mainly related to gestational age at birth.…”

“…The etiopathogenesis of PPROM is multifactorial. Disruption of histone and metalloproteinase balance, weakening of fetal membrane configuration, inflammation, and oxidative stress are some of the theories that may be associated factors 2–4 . Among the other causes of preterm birth, pregnancies with PPROM have the most adverse perinatal outcome.…”