scholarly journals Impact of sustained TGFβ receptor inhibition on chromatin accessibility and gene expression in cultured human endometrial MSC

2020 ◽  
Author(s):  
Raffaella Lucciola ◽  
Pavle Vrljicak ◽  
Caitlin Filby ◽  
Saeedeh Darzi ◽  
Shanti Gurung ◽  
...  
Keyword(s):  
Gene Expression ◽  
Retinoic Acid ◽  
Gene Networks ◽  
Large Scale ◽  
Transforming Growth Factor ◽  
Retinoic Acid Receptor ◽  
Human Endometrium ◽  
Acid Receptor ◽  
Genome Wide ◽  
The Impact

AbstractEndometrial mesenchymal stem cells (eMSC) drive the extraordinary regenerative capacity of the human endometrium. Clinical application of eMSC for therapeutic purposes is hampered by spontaneous differentiation and cellular senescence upon large-scale expansion in vitro. A83-01, a selective transforming growth factor-β receptor (TGFβ-R) inhibitor, promotes pharmacological expansion of eMSC in culture by blocking differentiation and senescence, but the underlying mechanisms are incompletely understood. In this study, we combined RNA-seq and ATAC-seq to study the impact of sustained TGFβ-R inhibition on gene expression and chromatin architecture of eMSC. Treatment of primary eMSC with A83-01 for 5 weeks resulted in differential expression of 1,463 genes. Gene ontology analysis showed enrichment of genes implicated in cell growth whereas extracellular matrix genes and genes involved in cell fate commitment were downregulated. ATAC-seq analysis demonstrated that sustained TGFβ-R inhibition results in opening and closure of 3,555 and 2,412 chromatin loci, respectively. Motif analysis revealed marked enrichment of retinoic acid receptor (RAR) binding sites, which was paralleled by the induction of RARB, encoding retinoic acid receptor beta (RARβ). Selective RARβ inhibition attenuated proliferation and clonogenicity of A83-01 treated eMSC. Taken together, our study provides new insights into the gene networks and genome-wide chromatin changes that underpin maintenance of an undifferentiated phenotype of eMSC in prolonged culture.Significance statementCycling human endometrium is a rich source of adult stem/progenitor cells that could be exploited for clinical purposes. Small molecules, such as A83-01, that modulate cell identity may open new avenues to maintain the functional properties of eMSC upon expansion in culture. By integrating complementary genome-wide profiling techniques, we mapped the dynamic changes in chromatin landscape and gene expression in response to prolonged A83-01 treatment of eMSC. Our findings provide new insights into the mechanisms of action of TGFβ-R inhibition that may lead to the development of more targeted pharmacological approaches for MSC expansion.

scholarly journals The Environmental Light Influences the Circulatory Levels of Retinoic Acid and Associates with Hepatic Lipid Metabolism

Endocrinology ◽  
2008 ◽  
Vol 149 (12) ◽  
pp. 6336-6342 ◽  
Author(s):  
Wenqiang Pang ◽  
Chunying Li ◽  
Yue Zhao ◽  
Shiming Wang ◽  
Wei Dong ◽  
...  
Keyword(s):  
Gene Expression ◽  
Retinoic Acid ◽  
Adenosine Receptors ◽  
Light Exposure ◽  
Retinoic Acid Receptor ◽  
Hepatic Lipase ◽  
Mouse Retina ◽  
Acid Receptor ◽  
Hepatic Lipid ◽  
Environmental Light

Environmental light is involved in the regulation of photochemical reaction in mouse retina. It remains unclear whether light-mediated increase in all-trans retinoic acid (ATRA) synthesis in retina will result in altering the circulatory levels of ATRA and regulating downstream gene expression and physiological function. Here we showed circulatory levels of ATRA decreased in mice under constant darkness and elevated by light exposure. Fat gene pancreatic lipase-related protein 2 (mPlrp2) and its partner procolipase (mClps), but not hepatic lipase (mHl), activated in livers for responding to lack of light illuminating. Light-triggered alterations in circulatory ATRA levels regulated ecto-5′-nucleotidase gene expression by retinoic acid receptor retinoic acid receptor-α and modulated 5′-AMP levels in blood and were associated with mPlrp2 and mClps expression in the livers. Mice deficient in adenosine receptors displayed mPlrp2 and mClps expression in livers under 12-h light, 12-h dark cycles. Caffeine blocked adenosine receptors and induced hepatic mPlrp2 and mClps expression in wild-type mice. Mice activated in hepatic mPlrp2 and mClps expression lowered hepatic and serum lipid levels and markedly elevated circulatory levels of all-trans retinol. Our results suggest environmental light influence hepatic lipid homeostasis by light-modulated retinoic acid signaling associated with mPlrp2 and mClps gene expression in livers.

scholarly journals Interplay of Protein Disorder in Retinoic Acid Receptor Heterodimer and Its Corepressor Regulates Gene Expression

Structure ◽  
2019 ◽  
Vol 27 (8) ◽  
pp. 1270-1285.e6 ◽  
Author(s):  
Tiago N. Cordeiro ◽  
Nathalie Sibille ◽  
Pierre Germain ◽  
Philippe Barthe ◽  
Abdelhay Boulahtouf ◽  
...  
Keyword(s):  
Gene Expression ◽  
Retinoic Acid ◽  
Retinoic Acid Receptor ◽  
Protein Disorder ◽  
Acid Receptor

scholarly journals Retinoic acid receptor-related orphan receptor (ROR) α4 is the predominant isoform of the nuclear receptor RORα in the liver and is up-regulated by hypoxia in HepG2 human hepatoma cells

2002 ◽  
Vol 364 (2) ◽  
pp. 449-456 ◽  
Author(s):  
Caroline CHAUVET ◽  
Brigitte BOIS-JOYEUX ◽  
Jean-Louis DANAN
Keyword(s):  
Gene Expression ◽  
Retinoic Acid ◽  
Hepg2 Cells ◽  
Transcriptional Activity ◽  
Cobalt Chloride ◽  
Retinoic Acid Receptor ◽  
Orphan Receptor ◽  
Human Hepatoma ◽  
Human Hepatoma Cells ◽  
Acid Receptor

The retinoic acid receptor-related orphan receptor α (RORα) is critically involved in many physiological functions in several organs. We find that the main RORα isoform in the mouse liver is the RORα4 isoform, in terms of both mRNA and protein levels, while the RORα1 isoform is less abundant. Because hypoxia is a major feature of liver physiology and pathology, we examined the effect of this stress on Rora gene expression and RORα transcriptional activity. HepG2 human hepatoma cells were cultured for 24h under normoxia (20% O2) or hypoxia (10, 2, and 0.1% O2) and the abundance of the Rora transcripts measured by Northern blot and semi-quantitative RT-PCR. Hypoxic HepG2 cells contained more Rora mRNA than controls. This was also observed in rat hepatocytes in primary culture. Cobalt chloride and desferrioxamine also increased the amount of Rora mRNA in HepG2 cells. It is likely that these treatments increase the amount of the RORα4 protein in HepG2 cells as evidenced by Western blotting in the case of desferrioxamine. Transient transfection experiments indicated that hypoxia, cobalt chloride, and desferrioxamine all stimulate RORα transcriptional activity in HepG2 cells. Hence, we believe that RORα participates in the control of gene transcription in hepatic cells and modulates gene expression in response to hypoxic stress.

scholarly journals Effect of retinoid status on α, β and γ retinoic acid receptor mRNA levels in various rat tissues

1992 ◽  
Vol 286 (3) ◽  
pp. 755-760 ◽  
Author(s):  
S Kato ◽  
H Mano ◽  
T Kumazawa ◽  
Y Yoshizawa ◽  
R Kojima ◽  
...  
Keyword(s):  
Gene Expression ◽  
Vitamin D ◽  
Retinoic Acid ◽  
Thyroid Hormone ◽  
Vitamin A ◽  
Retinoic Acid Receptor ◽  
Rat Tissues ◽  
Mrna Levels ◽  
Acid Receptor ◽  
Beta Gene

We have investigated the effects of retinoids, vitamin D and thyroid hormone on the levels of retinoic acid receptor (RAR)alpha, RAR beta and RAR gamma mRNAs in intact animals. Although vitamin A deficiency caused no significant changes in the levels of RAR alpha and RAR gamma mRNAs, the level of RAR beta transcripts was greatly decreased in various tissues of vitamin A-deficient rats, but was restored rapidly to a normal level after administration of retinoic acid. Retinol also restored the RAR beta mRNA level, but the magnitude and kinetics of the induction differed from those by retinoic acid. The use of specific inhibitors demonstrated that this autoregulation of RAR beta gene expression in vivo occurred at the transcriptional level. In addition, from these results it was postulated that the maintenance of the normal RAR beta mRNA levels seemed to require a threshold serum retinol concentration (about 25 micrograms/dl). Moreover, we found that administration of retinol and retinoic acid to normal rats caused the overexpression of RAR beta transcripts (2-15-fold) when compared with the control levels of RAR beta mRNA, although the levels of RAR alpha and RAR gamma mRNAs were not affected. Vitamin D and thyroid hormone did not modulate the levels of RAR transcripts. These findings clearly indicate the specific ligand regulation of RAR beta gene expression in intact animals. The altered levels of RAR beta according to retinoid status may affect retinoid-inducible gene expression.

Specific spatial and temporal distribution of retinoic acid receptor gamma transcripts during mouse embryogenesis

Development ◽  
1990 ◽  
Vol 108 (2) ◽  
pp. 213-222 ◽  
Author(s):  
E. Ruberte ◽  
P. Dolle ◽  
A. Krust ◽  
A. Zelent ◽  
G. Morriss-Kay ◽  
...  
Keyword(s):  
Gene Expression ◽  
Retinoic Acid ◽  
Retinoic Acid Receptor ◽  
Temporal Distribution ◽  
Spatial And Temporal Distribution ◽  
Mouse Development ◽  
Pharyngeal Arches ◽  
Acid Receptor ◽  
Squamous Epithelia

Retinoic acid (RA), a putative morphogen in vertebrates, has profound effects on development during embryogenesis, chondrogenesis and differentiation of squamous epithelia. The distribution of the transcripts of the retinoic acid receptor gamma (RAR-gamma) gene has been studied here by in situ hybridization during mouse development from days 6.5 to 15.5 post-coitum (p.c.). RAR-gamma transcripts are detected as early as day 8 p.c. in the presomitic posterior region. Between days 9.5 and 11.5 p.c., the transcripts are uniformly distributed in the mesenchyme of the frontonasal region, pharyngeal arches, limb buds and sclerotomes. At day 12.5 p.c., RAR-gamma transcripts are found in all precartilaginous mesenchymal condensations. From day 13.5 p.c., the transcripts are specifically localized in all cartilages and differentiating squamous keratinizing epithelia, irrespective of their embryological origin. RAR-gamma transcripts are also found in the developing teeth and whisker follicles. The developmental pattern of expression of the RAR-gamma gene suggests that RAR-gamma plays a crucial role for transducing RA signals at the level of gene expression during morphogenesis, chondrogenesis and differentiation of squamous epithelia.

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