Estrogen receptor alpha regulates the expression of adipogenic genes genetically and epigenetically in rat bone marrow-derived mesenchymal stem cells

Abstract

Regulation of the efficacy of epigenetic modifiers is regarded as an important control mechanism in the determination and differentiation of stem cell fate. Studies are showing that the effect of estrogen is important in the differentiation of mesenchymal stem cells (MSCs) into adipocytes, osteocytes, and chondrocytes. Activation of certain transcription factors and epigenetic modifications in related genes play an active role in the initiation and completion of adipogenic differentiation. Understanding the role of estrogen in diseases such as obesity, which increases with the onset of menopause, will pave the way for more effective use of estrogen as a therapeutic option. Demonstration of the differentiation tendencies of MSCs change in the presence/absence of estrogen, especially the evaluation of reversible epigenetic changes, will provide valuable information for clinical applications. In this study, the effect of estrogen on the expression of genes involved in adipogenic differentiation of MSCs and accompanying epigenetic modifications was investigated. Our results showed that estrogen affects the expression of adipogenesis-related transcription factors such as PPARy, C/EBPα and Adipsin. In addition, after estrogen treatment, increased accumulation of estrogen receptor alpha (ERα) and repressive epigenetic markers such as H3K27me2 and H3K27me3 were observed on the promoter of given transcription factors. By using co-immunoprecipitation experiments we were also able to show that ERα physically interacts with the zeste homolog 2 (EZH2) H3K27 methyltransferase in MSCs. We propose that the increase of H3K27me2 and H3K27me3 markers on adipogenic genes upon estrogen treatment may be mediated by the direct interaction of ERα and EZH2. Taken together, these findings suggest that estrogen has a role as an epigenetic switcher in the regulation of H3K27 methylation leading to suppression of adipogenic differentiation of MSC.

Metabolic and Epigenetic Regulation by Estrogen in Adipocytes

“…ERα mediates epigenetic silencing by recruiting histone deacetylase HDAC1 and HMTs like EZH2 to convert activating H3K27ac marks to repressive H3K27me3 marks ( 99 ) ( Figure 2A ). In rats, E2 treatment increased the binding of ERα/EZH2 to the promoters of Pparg , C/ebpa and Cfd (encoding Adipsin) in mesenchymal stem cells (MSCs), leading to increased H3K27 methylation and repression of these genes ( 112 ). These data support a predominantly inhibitory effect of estrogen on adipogenesis, and this effect is at least partly due to epigenetic silencing of adipogenic master regulators.…”

Bone marrow adipocyte: Origin, biology and relationship with hematological malignancy

“…Mechanically, direct interaction between estrogen receptor (Erα) and EZH2 decreases H3K27me2 and H3K27me3 levels of adipogenic genes, such as C/EBPα, PPARy, and Adipsin, thus indicating a suppressed role of estrogen in adipogenic differentiation. 30 Further, low estrogen levels are associated with high follicle-stimulating hormone (FSH) levels and collaboratively play a significant role in boosting core adipogenic genes. 31 Parathyroid hormone (PTH) is the most important osteogenic factor in human growth.…”

Post-Transcriptional and Epigenetic Regulation of Estrogen Signaling

“…These events may mediate the transgenerational inheritance of adipose tissue regulation and obesity (Sun et al, 2019). Moreover, ERα and/or ERβ are thought to be involved in the epigenetic regulation of adipogenesis (Bitirim et al, 2021). Histone modifications by ERα are described: for instance, ERα interacts with and promotes the activity of lysine methyltransferase 2B (MLL2), which is also required for ERα-activated gene transcription (Shi et al, 2011).…”