Differential ESR1 Promoter Methylation in the Peripheral Blood—Findings from the Women 40+ Healthy Aging Study

Abstract

Background Estrogen receptor α (ERα) contributes to maintaining biological processes preserving health during aging. DNA methylation changes of ERα gene (ESR1) were established as playing a direct role in the regulation of ERα levels. In this study, we hypothesized decreased DNA methylation of ESR1 associated with postmenopause, lower estradiol (E2) levels, and increased age among healthy middle-aged and older women. Methods We assessed DNA methylation of ESR1 promoter region from dried blood spots (DBSs) and E2 from saliva samples in 130 healthy women aged 40–73 years. Results We found that postmenopause and lower E2 levels were associated with lower DNA methylation of a distal regulatory region, but not with DNA methylation of proximal promoters. Conclusion Our results indicate that decreased methylation of ESR1 cytosine-phosphate-guanine island (CpGI) shore may be associated with conditions of lower E2 in older healthy women.

The high methylation level of a novel 151-bp CpG island in the ESR1 gene promoter is associated with a poor breast cancer prognosis

“…Our results suggested that methylation of this novel island depends on ER but not on the estrogen binding. As previously reported, methylation of ESR1 in proximal regulatory regions was not associated with estradiol levels [ 30 , 31 ]. Since the 151-bp island is in a proximal promoter, its degree of methylation might not be associated with estradiol levels.…”

The Swiss Perimenopause Study – study protocol of a longitudinal prospective study in perimenopausal women

“…For this purpose, we aim to investigate the estrogen receptor genes (ER1, ER2, GPER), the glucocorticoid receptor (NR3C1) as well as the serotonin transporter (5-HTTLPR) and the respective relationships with a resilient menopausal transition or the development of depression in the perimenopause. For example, a recent study by our workgroup found a positive relationship between the methylation of the ERα enhancer and depressed mood in women around the menopause [67]. Consequently, one goal is to investigate the autoregulation between estradiol and the estrogen receptor genes with regard to methylation patterns and subsequent effects on the participants' mood.…”

<p>Sleep and Methylation of Estrogen Receptor Genes, <em>ESR1</em> and <em>GPER</em>, in Healthy Middle-Aged and Older Women: Findings from the Women 40+ Healthy Aging Study</p>

“…[76][77][78] Using the online tool provided by Hannon et al (2015), 76 we found that methylation of CpGs located in the assessed DNA region of ESR1 was strongly correlated between blood and brain in the same individuals. 35 Therefore, methylation variations in blood may reflect methylation variations in the brain, for the assessed CpGs of ESR1.…”

“…Women who took part in this study were recruited in the context of a larger investigation, the "Women 40+ Healthy Aging Study". [33][34][35][36] Women were recruited using flyers, social media (eg: Facebook), and journal articles. The prospective participants completed an online selfscreening to verify their eligibility for the study.…”

“…(A) The DNA sequence of ESR1, chr6: 151805523-151805822, is located in a CpG island shore of promoter C, and it has been described as an enhancer (ID GH06J151804) of promoter A. 44 This region has been reported in humans and rats by Champagne et al, 2006, 23 Gardini et al, 2020, 35 Ianov et al, 2017, 46 and Tsuboi et al, 2017. 44 (B) The DNA sequence of GPER, chr7:1087059-1087533 is located in a CpG island across exons 1 and 2.…”