Regulation of human trophoblast syncytialization by histone demethylase LSD1

Abstract

A successful pregnancy is critically dependent upon proper placental development and function. During human placentation, villous cytotrophoblast (CTB) progenitors differentiate to form syncytiotrophoblasts (SynTBs), which provide the exchange surface between the mother and fetus and secrete hormones to ensure proper progression of pregnancy. However, epigenetic mechanisms that regulate SynTB differentiation from CTB progenitors are incompletely understood. Here, we show that lysine-specific demethylase 1 (LSD1; also known as KDM1A), a histone demethylase, is essential to this process. LSD1 is expressed both in CTB progenitors and differentiated SynTBs in first-trimester placental villi; accordingly, expression in SynTBs is maintained throughout gestation. Impairment of LSD1 function in trophoblast progenitors inhibits induction of endogenous retrovirally encoded genes SYNCYTIN1/endogenous retrovirus group W member 1, envelope (ERVW1) and SYNCYTIN2/endogenous retrovirus group FRD member 1, envelope (ERVFRD1), encoding fusogenic proteins critical to human trophoblast syncytialization. Loss of LSD1 also impairs induction of chorionic gonadotropin α (CGA) and chorionic gonadotropin β (CGB) genes, which encode α and β subunits of human chorionic gonadotrophin (hCG), a hormone essential to modulate maternal physiology during pregnancy. Mechanistic analyses at the endogenous ERVW1, CGA, and CGB loci revealed a regulatory axis in which LSD1 induces demethylation of repressive histone H3 lysine 9 dimethylation (H3K9Me2) and interacts with transcription factor GATA2 to promote RNA polymerase II (RNA-POL-II) recruitment and activate gene transcription. Our study reveals a novel LSD1–GATA2 axis, which regulates human trophoblast syncytialization.

Extensive Placental Methylation Profiling in Normal Pregnancies

“…The pattern of placental methylation is crucial for the regulation of genes involved in trophoblast invasion and placental development, which are key events for fetal growth [ 11 , 12 ]. For example, the expression of the gene encoding chorionic gonadotropin is related to the gestational week of pregnancy and its expression is epigenetically regulated [ 13 ].…”

Nucleoporin TPR Affects C2C12 Myogenic Differentiation via Regulation of Myh4 Expression

“…Thus, we hypothesize that TPR-targeted LSD1 might de-methylate TFs, such as MEF2D or MYOD1, at the Myh4 and Olfr376 promoters, as described by [ 24 ]. Another possibility is that LSD1 targets TFs to the TPR-associated genes, as shown for TF GATA2, which promotes RNA polymerase II recruitment and activates the transcription of genes crucial for the fusion of trophoblast cells into syncytiotrophoblasts [ 57 ]. Alternatively, the deregulation of Myh4 and Olfr376 in TPR-depleted cells could occur independently of LSD1, for instance through gene organization changes within the cell nucleus.…”

Placenta specific gene targeting to study histone lysine demethylase and androgen signaling in ruminant placenta

“…The knockout embryos also displayed morphological abnormalities such as smaller sizes and reduced trophoblast development compared to wildtype mice. In addition, a recent study using human choriocarcinoma (BeWo) cells revealed a role for KDM1A in cytotrophoblast differentiation into syncytiotrophoblasts by recruiting transcription factor GATA2 and stimulation of hCG production ( Milano-Foster et al., 2019 ).…”