Age-associated increase of thyroid hormone receptor β gene promoter methylation coexists with decreased gene expression

Pawlik-Pachucka, Eliza; Budzinska, Monika; Wicik, Zofia; Domaszewska-Szostek, Anna; Owczarz, Magdalena; Roszkowska-Gancarz, Małgorzata; Gewartowska, Magdalena; Puzianowska-Kuźnicka, Monika

doi:10.1080/07435800.2018.1469648

Cited by 8 publications

(6 citation statements)

References 55 publications

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“…The participation of TH-receptors in the regulation of ovarian function has also been observed in mouse models carrying a whole-body homozygous deletion of the TRs genes [51,52]. Our data are in agreement with previous studies showing the age-related decrease in THRB expression in other cell types (PBMC) as a result of the increased methylation of its promoter [53]. Further studies are necessary to characterize the molecular mechanism leading to their inhibition in ovaries.…”

Section: Discussionsupporting

confidence: 92%

A Cross-Species Analysis Reveals Dysthyroidism of the Ovaries as a Common Trait of Premature Ovarian Aging

Colella

Cuomo

Nittoli

et al. 2023

IJMS

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Although the imbalance of circulating levels of Thyroid Hormones (THs) affects female fertility in vertebrates, its involvement in the promotion of Premature Ovarian Aging (POA) is debated. Therefore, altered synthesis of THs in both thyroid and ovary can be a trait of POA. We investigated the relationship between abnormal TH signaling, dysthyroidism, and POA in evolutionary distant vertebrates: from zebrafish to humans. Ovarian T3 signaling/metabolism was evaluated by measuring T3 levels, T3 responsive transcript, and protein levels along with transcripts governing T3 availability (deiodinases) and signaling (TH receptors) in distinct models of POA depending on genetic background and environmental exposures (e.g., diets, pesticides). Expression levels of well-known (Amh, Gdf9, and Inhibins) and novel (miR143/145 and Gas5) biomarkers of POA were assessed. Ovarian dysthyroidism was slightly influenced by genetics since very few differences were found between C57BL/6J and FVB/NJ females. However, diets exacerbated it in a strain-dependent manner. Similar findings were observed in zebrafish and mouse models of POA induced by developmental and long-life exposure to low-dose chlorpyrifos (CPF). Lastly, the T3 decrease in follicular fluids from women affected by diminished ovarian reserve, as well as of the transcripts modulating T3 signaling/availability in the cumulus cells, confirmed ovarian dysthyroidism as a common and evolutionary conserved trait of POA.

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Section: Discussionsupporting

confidence: 92%

A Cross-Species Analysis Reveals Dysthyroidism of the Ovaries as a Common Trait of Premature Ovarian Aging

Colella

Cuomo

Nittoli

et al. 2023

IJMS

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“…On the receptor level, no effect of age on Thra was observed, while a progressive increase in Thrb mRNA and total TRβ protein level was found in old rats; however, most remarkably, the nuclear levels of TRβ seemed to decline (35). Data on the human situation are scarce, reporting only an age-dependent decrease in THRB expression in peripheral blood mononuclear cells, presumably driven by changes in promoter methylation (38). Consequently, our data on decreased hepatic THRB and DIO1 expression are of explicit biological relevance for the understanding of TH economy in the aging liver, as they suggest that the liver might become somewhat resistant to circulating TH.…”

Section: Discussionmentioning

confidence: 99%

Reduced expression of thyroid hormone receptor β in human nonalcoholic steatohepatitis

Krause

Grohs

Gammal

et al. 2018

Endocrine Connections

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Hepatic thyroid hormone signaling has an important role in the development and progression of nonalcoholic steatohepatitis (NASH). While the systemic levels of thyroid hormone might remain stable, there is evidence that the intracellular signaling machinery consisting of transporters, deiodinases and receptors could be altered in NASH. However, clinical material from human liver biopsies of individuals with NASH has not been studied to date. In a cross-sectional study, we analyzed 85 liver biopsies from patients with different stages of NASH that underwent bariatric surgery. Using qPCR, we analyzed gene expression of thyroid hormone transporters NTCP (SLC10A1), MCT8 (SLC16A2) and OATP1C1 (SLCO1C1), thyroid hormone receptor α and β (THRA and THRB) and deiodinase type I, II and III (DIO1, DIO2, DIO3). The expression was correlated with serum TSH, triglyceride, HbA1c and NASH score and corrected for age or gender if required. While DIO2, DIO3 and SLCO1C1 were not expressed in human liver, we observed a significant negative correlation of THRB and DIO1 with age, and SLC16A2 with gender. THRB expression was also negatively associated with serum triglyceride levels and HbA1c. More importantly, its expression was inversely correlated with NASH score and further declined with age. Our data provide unique insight into the mRNA expression of thyroid hormone transporters, deiodinases and receptors in the human liver. The findings allow important conclusions on the intrahepatic mechanisms governing thyroid hormone action, indicating a possible tissue resistance to the circulating hormone in NASH, which becomes more prominent in advanced age.

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“…Thyroid hormone receptors are coded by two genes: alfa and beta. The epigenetic regulation of THRB has previously been shown to be involved in many human phenotypes such as cancer, obesity, and aging (Joseph et al 2007; Ling et al 2010; Kim et al 2013; Pawlik-Pachucka et al 2018; Shimi et al 2022), and affected by exposures to e.g. thyroid hormones and environmental toxins in mice (Cho et al 2021; Laufer et al 2022), and thus we were interested in investigating if that is the case also in the context of avian maternal hormones, and chose THRB for the methylation analyses.…”

Section: Methodsmentioning

confidence: 99%

From maternal glucocorticoid and thyroid hormones to epigenetic regulation of gene expression: an experimental study in a wild bird species

Hukkanen

Hsu

Cossin-Sevrin

et al. 2023

Preprint

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Offspring phenotype at birth is determined by its genotype and the prenatal environment including exposure to maternal hormones. Variation in both maternal glucocorticoids and thyroid hormones can affect offspring phenotype. However, the underlying molecular mechanisms shaping the offspring phenotype, especially those contributing to long-lasting effects, remain unclear. Epigenetic changes (such as DNA methylation) have been postulated as mediators of long-lasting effects of early-life environment. In this study, we determined the effects of elevated prenatal glucocorticoid and thyroid hormones on handling stress response (breath rate), DNA methylation and gene expression of glucocorticoid receptor (GCR) and thyroid hormone receptor (THR) in great tit (Parus major). Eggs were injected before incubation onset with corticosterone (main avian glucocorticoid) and/or thyroid hormones (thyroxine and triiodothyronine) to simulate variation in maternal hormone deposition. Breath rate during handling and gene expression of GCR and THR were evaluated 14 days after hatching. Methylation status of GCR and THR genes were analyzed from the longitudinal blood samples taken 7 and 14 days after hatching, as well as in the following autumn. Elevated prenatal corticosterone level significantly increased the breath rate during handling, indicating enhanced stress response and/or metabolism. Prenatal corticosterone manipulation had CpG-site-specific effects on DNA methylation at the GCR putative promoter region, while it did not significantly affect GCR gene expression. GCR expression was negatively associated with earlier hatching date and chick size. THR methylation or expression did not exhibit any significant relationship with the hormonal treatments or the examined covariates, suggesting that TH signaling may be more robust due to its crucial role in development. This study supports the view that maternal corticosterone may influence offspring metabolism and stress response via epigenetic alterations, yet their possible adaptive role in optimizing offspring phenotype to the prevailing conditions, context-dependency, and the underlying molecular interplay needs further research.

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Age-associated increase of thyroid hormone receptor β gene promoter methylation coexists with decreased gene expression

Abstract: Age-related decrease of THRB expression in PBMC of elderly and long-lived humans might be, in part, a result of the increased methylation of its promoter, but is unrelated to the activity of the miRNAs analyzed here.

Cited by 8 publications

References 55 publications

A Cross-Species Analysis Reveals Dysthyroidism of the Ovaries as a Common Trait of Premature Ovarian Aging

A Cross-Species Analysis Reveals Dysthyroidism of the Ovaries as a Common Trait of Premature Ovarian Aging

Reduced expression of thyroid hormone receptor β in human nonalcoholic steatohepatitis

From maternal glucocorticoid and thyroid hormones to epigenetic regulation of gene expression: an experimental study in a wild bird species

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