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.
Highlights
Cell fusion into a syncytium is the process whereby several cells coalesce to form a multinucleated entity, and features in homeostasis of several normal tissues and pathologies[1,2]
We found that histone acetylation decreases as trophoblast cells and cell lines differentiate into syncytiotrophoblast, and that HDAC1 and HDAC2 activity is required for cytotrophoblast differentiation
Since images represent a snapshot of the human placenta and we cannot confirm the developmental stage of each cell, we sought to analyze histone acetylation patterns in primary cytotrophoblasts, Fig. 1 Histone acetylation patterns in human placenta and primary cytotrophoblasts. a Localization of acetylated histone H2B K5 (AcH2BK5), AcH3K9, AcH3K27, AcH3K14, and AcH3K18 in 6-week and 39-week human placenta
Summary
Cell fusion into a syncytium is the process whereby several cells coalesce to form a multinucleated entity, and features in homeostasis of several normal tissues and pathologies (e.g., cancer, virus infection, inflammation)[1,2]. One of the best paradigms of syncytium formation occurs in the placenta—the organ that forms the interface between a pregnant mother and her baby. Official journal of the Cell Death Differentiation Association. Jaju Bhattad et al Cell Death and Disease (2020)11:311 nuclei demonstrating an open euchromatic appearance and others possessing a more heterochromatic state. Previous studies have indicated that syncytiotrophoblast nuclei are transcriptionally inert based on assessing uptake of [3H]-uridine, which correlates with the high number of heterochromatic nuclei[8,9]. Follow-up studies show that at least some nuclei are transcriptionally active[10]. These studies infer that cytotrophoblast progression into syncytiotrophoblast is associated with altered chromatin dynamics, which may be required for the robust changes in transcription required for syncytiotrophoblast formation and function
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
