Histone deacetylase 1 and 2 drive differentiation and fusion of progenitor cells in human placental trophoblasts

Abstract

Cell fusion occurs when several cells combine to form a multinuclear aggregate (syncytium). In human placenta, a syncytialized trophoblast (syncytiotrophoblast) layer forms the primary interface between maternal and fetal tissue, facilitates nutrient and gas exchange, and produces hormones vital for pregnancy. Syncytiotrophoblast development occurs by differentiation of underlying progenitor cells called cytotrophoblasts, which then fuse into the syncytiotrophoblast layer. Differentiation is associated with chromatin remodeling and specific changes in gene expression mediated, at least in part, by histone acetylation. However, the epigenetic regulation of human cytotrophoblast differentiation and fusion is poorly understood. In this study, we found that human syncytiotrophoblast development was associated with deacetylation of multiple core histone residues. Chromatin immunoprecipitation sequencing revealed chromosomal regions that exhibit dynamic alterations in histone H3 acetylation during differentiation. These include regions containing genes classically associated with cytotrophoblast differentiation (TEAD4, TP63, OVOL1, CGB), as well as near genes with novel regulatory roles in trophoblast development and function, such as LHX4 and SYDE1. Prevention of histone deacetylation using both pharmacological and genetic approaches inhibited trophoblast fusion, supporting a critical role of this process for trophoblast differentiation. Finally, we identified the histone deacetylases (HDACs) HDAC1 and HDAC2 as the critical mediators driving cytotrophoblast differentiation. Collectively, these findings provide novel insights into the epigenetic mechanisms underlying trophoblast fusion during human placental development.

Placental energy metabolism in health and disease—significance of development and implications for preeclampsia

“…Consistent with this hypothesis, cytotrophoblasts exhibit higher glycolytic metabolism than their differentiated syncytiotrophoblasts, 70 and higher histone acetylation levels. 71 Moreover, the loss of the HDAC SIRT1 in mice results in trophoblast differentiation failure and reduced fetal and placental weights. 71…”

“…71 Moreover, the loss of the HDAC SIRT1 in mice results in trophoblast differentiation failure and reduced fetal and placental weights. 71…”

Data-Driven Modeling of Pregnancy-Related Complications

“…While genetic contributions to different complications in pregnancy are probably polygenic, genome-wide association studies (GWASs) have found genetic variants associated specifically with sPTB, illustrating how a mother's genetic makeup can set the stage for fetal development and pregnancy outcome even before conception [71][72][73]. By contrast, maternal epigenetic modifications reflect the state of different cell types across tissues as they reprogram to prepare for fetal growth [74,75]. Quantification of these modificationsby measuring DNA methylation, histone markers, and chromatin accessibility in the cell subsets of interestoffers insights into whether different cell types in the maternal-fetal interface are adapting properly for a successful pregnancy [76,77].…”

Mitotic H3K9ac is controlled by phase-specific activity of HDAC2, HDAC3 and SIRT1

“…To determine which of the three HDACs (HDAC1, HDAC2 or HDAC10) is modulating H3K9ac during prophase, we used two specific inhibitors -MS-275 that specifically targets HDAC1, HDAC2 and HDAC3 (Khan et al, 2008, Tatamiya, Saito et al, 2004 and CAY10683, an HDAC2 inhibitor (Jaju Bhattad, Jeyarajah et al, 2020, Pavlik, Wong et al, 2013. Following the specific inhibition, we measured H3K9ac levels in cells captured at different stages of mitosis (Fig.…”