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

PeerJ ◽  
2021 ◽  
Vol 9 ◽  
pp. e12071
Author(s):  
Ceylan V. Bitirim ◽  
Zeynep B. Ozer ◽  
Kamil C. Akcali
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Estrogen Receptor ◽  
Transcription Factors ◽  
Cell Fate ◽  
Estrogen Receptor Alpha ◽  
Adipogenic Differentiation ◽  
Epigenetic Modifications ◽  
Estrogen Treatment ◽  
Receptor Alpha

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.

scholarly journals Integration of RNA-seq and Ribosome Profiling to Characterize Transcriptional and Translational Estrogen Responses of Genes in Human Breast Cancer

2020 ◽  
Author(s):  
Siew Woh Choo ◽  
Yu Zhong ◽  
Edward Sendler ◽  
Anton Scott Goustin ◽  
Juan Cai ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Estrogen Receptor Alpha ◽  
Ribosome Profiling ◽  
Estrogen Treatment ◽  
Differentially Expressed ◽  
Significant Advance ◽  
Rna Seq ◽  
Protein Coding ◽  
Receptor Alpha

Abstract BackgroundEstrogen is a hormone that is frequently essential in breast cancer to drive key transcriptional programs by interacting with the estrogen receptor alpha that upregulates proliferative and oncogenic genes and represses apoptotic and tumor suppressor genes. Protein-coding targets of estrogen regulation in breast cancer are well-defined. However, long non-coding RNA (lncRNA) genes account for the majority of human gene catalogs. The coding status of these genes – their accidental, or regulated, translation by ribosomes, under the influence of estrogen – remains a controversial topic. MethodsHere, we performed comprehensive transcriptome analysis using RNA-Seq, as well as ribosome profiling using Ribo-Seq, on the same samples: biological replicates of human estrogen receptor alpha (ERa) positive MCF7 breast cancer cells before and after estrogen treatment. We correlated these two datasets, globally highlighting protein-coding and lncRNA differentially expressed genes and transcripts that were positively as well as negatively responsive to estrogen, separately at the transcriptional level and the translational (as approximated by ribosome binding) level.ResultsOur data showed that some transcripts were more robustly detected in RNA-Seq than in the ribosome-profiling data, and vice versa, suggesting distinct gene-specific estrogen responses at the transcriptional and the translational level, respectively. Certain differentially expressed transcripts may point to the regulation of alternative splicing by estrogen. Several pseudogenes were co- and anti-regulated with their cancer-functional parental genes. Gene ontology analysis highlighted cancer-relevant pathways enriched after estrogen treatment in cells.ConclusionsOur study represents a significant advance in the estrogen receptor biology, because we demonstrated global effects of estrogen on splicing and translation that are distinct from, and not always correlated with, its effects on transcription, and that differ globally for protein-coding and lncRNA genes. We have also highlighted for the first time the transcriptional and translational response of expressed pseudogenes to estrogen, pointing to new perspectives for biomarker and drug-target development for breast cancer in future.

scholarly journals The role of total and cartilage-specific estrogen receptor alpha expression for the ameliorating effect of estrogen treatment on arthritis

2014 ◽  
Vol 16 (4) ◽  
pp. R150 ◽  
Author(s):  
Cecilia Engdahl ◽  
Anna E Börjesson ◽  
Huamei F Forsman ◽  
Annica Andersson ◽  
Alexandra Stubelius ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Estrogen Receptor Alpha ◽  
Estrogen Treatment ◽  
Receptor Alpha ◽  
And Cartilage

scholarly journals Ca2+-activated mitochondrial biogenesis and functions improve stem cell fate in Rg3-treated human mesenchymal stem cells

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Taeui Hong ◽  
Moon Young Kim ◽  
Dat Da Ly ◽  
Su Jung Park ◽  
Young Woo Eom ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Stem Cell ◽  
Cell Fate ◽  
Mitochondrial Biogenesis ◽  
Biological Activities ◽  
Adipogenic Differentiation ◽  
Human Mesenchymal Stem Cells ◽  
Stem Cell Fate ◽  
Mitochondrial Functions

Abstract Although mitochondrial functions are essential for cell survival, their critical roles in stem cell fate, including proliferation, differentiation, and senescence, remain elusive. Ginsenoside Rg3 exhibits various biological activities and reportedly increases mitochondrial biogenesis and respiration. Herein, we observed that Rg3 increased proliferation and suppressed senescence of human bone marrow-derived mesenchymal stem cells. Osteogenic, but not adipogenic, differentiation was facilitated by Rg3 treatment. Rg3 suppressed reactive oxygen species production and upregulated mitochondrial biogenesis and antioxidant enzymes, including superoxide dismutase. Consistently, Rg3 strongly augmented basal and ATP synthesis-linked respiration with high spare respiratory capacity. Rg3 treatment elevated cytosolic Ca2+ concentration contributing to mitochondrial activation. Reduction of intracellular or extracellular Ca2+ levels strongly inhibited Rg3-induced activation of mitochondrial respiration and biogenesis. Taken together, Rg3 enhances capabilities of mitochondrial and antioxidant functions mainly through a Ca2+-dependent pathway, which improves the proliferation and differentiation potentials and prevents the senescence of human mesenchymal stem cells.

scholarly journals Obesity-Associated MiR-342-3p Promotes Adipogenesis of Mesenchymal Stem Cells by Suppressing CtBP2 and Releasing C/EBPα from CtBP2 Binding

2015 ◽  
Vol 35 (6) ◽  
pp. 2285-2298 ◽  
Author(s):  
Liang Wang ◽  
Lei Xu ◽  
Min Xu ◽  
Guoqiang Liu ◽  
Jian Xing ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Transcription Factors ◽  
Western Blot ◽  
Metabolic Diseases ◽  
Adipogenic Differentiation ◽  
Luciferase Reporter ◽  
Loss Of Function ◽  
Qrt Pcr ◽  
Obesity And Diabetes

Background/Aims: The elucidation of the molecular mechanism of adipocyte differentiation in mesenchymal stem cells is of essential importance for the development of treatments for metabolic diseases, such as obesity and diabetes. Methods: The expression levels of miR-342-3p and carboxy-terminal binding protein 2 (CtBP2) were regulated by oligonucleotide transfection. Adipogenic differentiation was induced by adipogenic medium containing indomethacin, dexamethasone and 3-isobutyl-1-methylxanthine on day 12, as determined by Oil Red O staining and triglyceride concentration assay to assess intracellular lipid accumulation. The induction of adipocyte-specific transcription factors and markers was detected by qRT-PCR and western blot. The regulation of CtBP2 expression by miR-342-3p was determined by western blot, qRT-PCR, luciferase reporter assay, ChIP assay and functional experiments. Results: We revealed that miR-342-3p was enriched in the adipose tissue of obese mice, and its expression was significantly elevated during adipogenic differentiation in both human mesenchymal stem cells (hMSCs) and 3T3L1 cells. Using gain- and loss-of-function assays, we demonstrated that the overexpression of miR-342-3p markedly promoted the differentiation of hMSCs into an adipogenic lineage. Adipogenesis was significantly blocked by miR-342-3p downregulation. We identified and validated that CtBP2 was a direct target of miR-342-3p in this process. The effects of the inhibition of CtBP2 were similar to those of miR-342-5p overexpression on adipogenic differentiation, promoting the release of C/EBPα from CtBP2 binding. Conclusion: miR-342-3p is a powerful enhancer of the adipogenesis of human adipose-derived MSCs that acts by inhibiting CtBP2 and releasing the key adipogenic regulator C/EBPα from CtBP2 binding, subsequently activating the expression of adipogenic transcription factors and markers.

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