Single CpG site methylation controls estrogen receptor gene transcription and correlates with hormone therapy resistance

Tsuboi, Kouki; Nagatomo, Takao; Gohno, Tatsuyuki; Higuchi, Toru; Sasaki, Shunta; Fujiki, N. M.; Kurosumi, Masafumi; Takei, Hiroyuki; Yamaguchi, Yuri; Niwa, Toshimitsu; Hayashi, Shin Ichi

doi:10.1016/j.jsbmb.2017.04.001

Cited by 46 publications

(55 citation statements)

References 39 publications

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“…Methylation of CpG islands has been shown to inhibit transcription by preventing the binding of transcription factors to the promoter or by stabilizing structural changes in chromatin that prevent transcription [ 123 ]. The absence of ERα gene expression in ERα-negative breast cancer cells is associated with abnormal methylation in the CpG islands of multipe promoters of the ERα gene [ 124 , 125 ]. Mechanistically, methylation of ERα promotet may prevent the recruitment of transcription factor such as AP2.…”

Section: Epigenetic Regulation Of Er Expressionmentioning

confidence: 99%

Mechanisms for estrogen receptor expression in human cancer

et al. 2018

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Estrogen is a steroid hormone that has critical roles in reproductive development, bone homeostasis, cardiovascular remodeling and brain functions. However, estrogen also promotes mammary, ovarian and endometrial tumorigenesis. Estrogen antagonists and drugs that reduce estrogen biosynthesis have become highly successful therapeutic agents for breast cancer patients. The effects of estrogen are largely mediated by estrogen receptor (ER) α and ERβ, which are members of the nuclear receptor superfamily of transcription factors. The mechanisms underlying the aberrant expression of ER in breast cancer and other types of human tumors are complex, involving considerable alternative splicing of ERα and ERβ, transcription factors, epigenetic and post-transcriptional regulation of ER expression. Elucidation of mechanisms for ER expression may not only help understand cancer progression and evolution, but also shed light on overcoming endocrine therapy resistance. Herein, we review the complex mechanisms for regulating ER expression in human cancer.

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Section: Epigenetic Regulation Of Er Expressionmentioning

confidence: 99%

Mechanisms for estrogen receptor expression in human cancer

et al. 2018

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“…However, in many instances multiple regulatory regions are present within these genomic intervals and the relationship of their activity to average DNA methylation within an interval unknown. This is further complicated by the observations that the methylation state of a single CpG can affect transcription ( Banet et al., 2000 , Fürst et al., 2012 , Hashimoto et al., 2013 , Jinno et al., 1995 , Mamrut et al., 2013 , Nile et al., 2008 , Tsuboi et al., 2017 , Zhou et al., 2017 ) by altering transcription factor binding affinity ( Rishi et al., 2010 , Yin et al., 2017 ). Imputation strategies leverage sequence context along with CpG methylation states across single cells to increase the resolution of genomic intervals ( Angermueller et al., 2017 ).…”

Section: Introductionmentioning

confidence: 99%

High-Resolution Single-Cell DNA Methylation Measurements Reveal Epigenetically Distinct Hematopoietic Stem Cell Subpopulations

et al. 2018

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SummaryIncreasing evidence of functional and transcriptional heterogeneity in phenotypically similar cells examined individually has prompted interest in obtaining parallel methylome data. We describe the development and application of such a protocol to index-sorted murine and human hematopoietic cells that are highly enriched in their content of functionally defined stem cells. Utilizing an optimized single-cell bisulfite sequencing protocol, we obtained quantitative DNA methylation measurements of up to 5.7 million CpGs in single hematopoietic cells. In parallel, we developed an analytical strategy (PDclust) to define single-cell DNA methylation states through pairwise comparisons of single-CpG methylation measurements. PDclust revealed that a single-cell epigenetic state can be described by a small (<1%) stochastically sampled fraction of CpGs and that these states are reflective of cell identity and state. Using relationships revealed by PDclust, we derive near complete methylomes for epigenetically distinct subpopulations of hematopoietic cells enriched for functional stem cell content.

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“…However, there is increasing evidence for the importance of the methylation status of individual cpG sites in the regulation of gene expression. For example, the methylation levels of a single cpG site was inversely correlated with oestrogen receptor α positivity in breast cancer specimens in a previous study (49). CpG site-specific methylation was demonstrated to alter the binding affinities of specific transcription factors that can activate or repress transcription (55,56).…”

Section: Discussionmentioning

confidence: 96%

Methylation status of CpG sites in the NOTCH4 promoter region regulates NOTCH4 expression in patients with tetralogy of Fallot

Zhu

et al. 2020

Mol Med Rep

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Tetralogy of Fallot (ToF) is the most common form of cyanotic congenital heart disease (cHd). although a lower methylation level of whole genome has been demonstrated in ToF patients, little is known regarding the dna methylation changes in specific gene and its associations with TOF development. noTcH4 is a mediator of the notch signalling pathway that plays an important role in normal cardiac development. However, the role of epigenetic regulation of the NOTCH4 gene in the pathogenesis of ToF remains unclear. considering the NOTCH4 low mutation frequency and reduced expression in the ToF patients, we hypothesized that abnormal dna methylation change of NOTCH4 gene may influence its expression and responsible for TOF development. in this study, we measured the promoter methylation status of NOTCH4 and was measured and its regulation mechanism was explored, which may be related to ToF disease. additionally, the promoter methylation statuses of NOTCH4 was measured in order to further understand epigenetic mechanisms that may serve a role in the development of ToF. immunohistochemical analysis was used to examine noTcH4 expression in right ventricular outflow tract myocardial tissues in patients with ToF. compared with healthy controls, patients with ToF displayed significantly reduced in noTcH4 expression (P=0.0055). Moreover, bisulphite sequencing suggested that the methylation levels of cpG site 2 in the NOTCH4 promoter was significantly higher in the patients than in the controls (P=0.0459). noTcH4 expression was negatively associated with cpG site 2 methylation levels (r=-0.51; P=0.01). eTS1 transcription factor can serve as transcriptional activators by binding to specific DNA sequences of target genes, such as DLL4 and NOTCH4, which serves an important role in normal heart development. dual-luciferase reporter and electrophoretic mobility shift assays indicated that the eTS1 transcription factor could bind to the NOTCH4 promoter region. However, binding of eTS1 to the NOTCH4 promoter was abrogated by methylation at the putative ETS1 binding sites. These findings suggested that decreased noTcH4 expression in patients with ToF may be associated with hypermethylation of cpG site 2 in the NOTCH4 promoter region, due to impaired binding of eTS1.

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Single CpG site methylation controls estrogen receptor gene transcription and correlates with hormone therapy resistance

Cited by 46 publications

References 39 publications

Mechanisms for estrogen receptor expression in human cancer

Mechanisms for estrogen receptor expression in human cancer

High-Resolution Single-Cell DNA Methylation Measurements Reveal Epigenetically Distinct Hematopoietic Stem Cell Subpopulations

Methylation status of CpG sites in the NOTCH4 promoter region regulates NOTCH4 expression in patients with tetralogy of Fallot

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