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.
Highlights
A successful pregnancy is critically dependent upon proper placental development and function
We started our study by looking at lysine-specific demethylase 1 (LSD1) expression during human placentation
We found that in a first-trimester human placenta, LSD1 is abundantly expressed in both CTB progenitors and differentiated SynTBs (Fig. 1A)
Summary
SynTB, syncytiotrophoblast; CTB, cytotrophoblast; LSD1, lysine-specific demethylase 1; ERVW1, endogenous retrovirus group W member 1, envelope; ERVFRD1, endogenous retrovirus group FRD member 1, envelope; CG, chorionic gonadotropin; hCG, human chorionic gonadotrophin; H3K9Me2, histone H3 lysine 9 dimethylation; RNAPOL-II, RNA polymerase II; PKA, protein kinase A; TSC, trophoblast stem cell; CoREST, corepressor to the transcription factor REST; NuRD, nucleosome remodeling and deacetylase; AR, androgen receptor; ER, estrogen receptor; 8-Br-cAMP, 8-bromo-cAMP; KD, knocked down expression of a gene; H3K27Me3, histone H3 lysine 27 trimethylation. We tested the importance of LSD1 via loss-of-function analyses and confirmed an essential role of LSD1 in human SynTB differentiation
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