Glucocorticoid receptor gene expression and promoter CpG modifications throughout the human brain

Cao-Lei, Lei; Suwansirikul, Songkiet; Jutavijittum, Prapan; Mériaux, Sophie B.; Turner, Jonathan D.

doi:10.1016/j.jpsychires.2013.07.022

Cited by 35 publications

(45 citation statements)

References 44 publications

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“…However, this was not observed in other related paradigms such as maternal separation [63] and feeding a methylation supplementation diet [64]. In humans, hippocampal CpG modifications of the orthologous 1F region was equally low [44,[65][66][67][68]. Nevertheless, methylation of a CpG in a separate upstream NGFI-A binding site was observed to correlate with prior childhood abuse in postmortem hippocampal tissue of suicide victims.…”

Section: State Of the Evidence For Nr3c1mentioning

confidence: 88%

“…Grey bars, the assay from Turner et al [84] that has been used by CaoLei et al [68], Labonté et al [40] and modified by Alt et al [67] (black bars); the assay from McGowan et al [41] that has additionally been used by Melas et al [43], Yehuda et al [20,55] (white bar); and the assay from Oberlander et al [23] that has also been used by Tyrka et al [44] and Perroud et al [46] (shaded bar). The vertical grey bar corresponds to the NGFI-A binding site within promoter 1F.…”

Section: Figure 1 Dna Methylation Analyses Of Nr3c1 Cpg Islands (A)mentioning

confidence: 99%

“…Nevertheless, methylation of a CpG in a separate upstream NGFI-A binding site was observed to correlate with prior childhood abuse in postmortem hippocampal tissue of suicide victims. Interpretation and comparison of the significance of single CpG methylation is further complicated by the fact that there are only few CpGs common in many of these studies (Figure 1) [40,41,66,68,69]. The number of CpGs investigated varies between studies, and only once a multiple testing correction was applied [68].…”

Section: State Of the Evidence For Nr3c1mentioning

confidence: 99%

“…Interpretation and comparison of the significance of single CpG methylation is further complicated by the fact that there are only few CpGs common in many of these studies (Figure 1) [40,41,66,68,69]. The number of CpGs investigated varies between studies, and only once a multiple testing correction was applied [68]. It is likely that in the majority of studies, associations would be rendered nonsignificant after correction for multiple testing.…”

Section: State Of the Evidence For Nr3c1mentioning

confidence: 99%

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Traumatic Stress and Human DNA Methylation: A Critical Review

et al. 2015

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Animal studies have identified persistent and functional effects of traumatic stress on the epigenome. This review discusses the clinical evidence for trauma-induced changes in DNA methylation across the life span in humans. Studies are reviewed based on reports of trauma exposure during the prenatal period (13 studies), early life (20 studies), and adulthood (ten studies). Even though it is apparent that traumatic stress influences the human epigenome, there are significant drawbacks in the existing human literature. These include a lack of longitudinal studies, methodological heterogeneity, selection of tissue type, and the influence of developmental stage and trauma type on methylation outcomes. These issues are discussed in order to present a way in which future studies can gain more insight into the functional relevance of trauma-related DNA methylation changes. Epigenetic studies investigating the detrimental effects of traumatic stress have great potential for an improved detection and treatment of trauma-related psychiatric disorders.

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Section: State Of the Evidence For Nr3c1mentioning

confidence: 88%

Section: Figure 1 Dna Methylation Analyses Of Nr3c1 Cpg Islands (A)mentioning

confidence: 99%

Section: State Of the Evidence For Nr3c1mentioning

confidence: 99%

Section: State Of the Evidence For Nr3c1mentioning

confidence: 99%

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Traumatic Stress and Human DNA Methylation: A Critical Review

et al. 2015

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“…It is reported that the status of DNA methylation in GR promoters is closely associated with the transcription of GR exon 1 mRNA variants (Turner et al, 2010) in human brain (Cao-Lei et al, 2013) and hippocampus (McGowan et al, 2009). In this study, the methylation status of individual CpG site on GR promoters was profiled.…”

Section: Discussionmentioning

confidence: 95%

Breed-specific expression of GR exon 1 mRNA variants and profile of GR promoter CpG methylation in the hippocampus of newborn piglets

Sun

Jia

et al. 2014

Animal

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Glucocorticoid receptor (GR) transcription is driven by alternative promoters to produce different exon 1 mRNA variants. CpG methylation on GR promoters profoundly affects GR transcription. GR in hippocampus is critical for energy homeostasis and stress responses, yet it remains unclear whether hippocampal expression of GR exon 1 mRNA variants and the methylation status of GR promoters differ between Large White (LW) and Erhualian (EHL) pigs showing distinct metabolic and stress-coping characteristics. EHL pigs had higher hippocampus weight relative to BW ( P < 0.01), which was associated with higher serum cortisol level compared with LW pigs. Hippocampal expression of brain-derived neurotrophic factor ( P < 0.05) was significantly higher, while Bax, a pro-apoptotic gene, was significantly lower in EHL pigs ( P < 0.05). Hippocampal expression of total GR did not differ between breeds, yet GR exon 1 to 11 mRNA was significantly higher ( P < 0.01) in EHL pigs, which was associated with a trend of increase ( P = 0.057) in GR protein content. No significant breed difference was detected for the methylation status across the whole region of the proximal GR promoter, while CpG334 and CpG266.267 were differentially methylated, in a reversed manner, between breeds. The methylation status of CpGs 248, 259, 260, 268 and 271 was negatively correlated ( P < 0.05) with GR exon 1 to 11 mRNA abundance. Our results provide fundamental information on the breed-specific characteristics of GR and its mRNA variants expression and the status of DNA methylation on the proximal GR promoter in the pig hippocampus.

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The N‐terminal transactivation domain of the glucocorticoid receptor mediates apoptosis of human small cell lung cancer cells

Singh

Taylor

Mjoli

et al. 2014

Genes Chromosomes & Cancer

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Small cell lung cancer (SCLC) is an aggressive disease with a poor prognosis. These cancers are deficient in glucocorticoid receptor (GR) expression, and therefore, resistant to glucocorticoids. Overexpression of the GR both in vivo and in vitro leads to apoptotic cell death suggesting that loss of GR is favorable for cancer growth. Indeed, the GR promoter is silenced in SCLC cells by methylation. We now show that treatment of the SCLC cell line (DMS79) cells with the demethylating agent, 5-aza-2'-deoxycytidine (5-aza), results in significant endogenous re-expression of both GRα and the ligand-independent GR-P. The GR gene has a complex promoter region comprising nine alternative promoters, the proximal seven of which lie within a CpG island. The endogenous re-expression seen is attributed to the constitutive promoters 1B and 1C and 1J but predominantly 1F, which we show to be heavily methylated in SCLC cells. Flow cytometric analysis using the apoptotic marker, Annexin V, shows that this endogenous re-expression is sufficient to drive the SCLC cells to apoptosis. Apoptotic induction is specific to GR re-expression as cotreatment with 5-aza and the GR antagonist, RU486 prevented apoptosis. Of the three functional GR domains (the DNA binding domain, ligand binding domain, and transactivation domain), we identified that the transactivation domain is essential for apoptosis in SCLC. The discovery that endogenous re-expression of the GR in SCLC cells is sufficient to induce apoptotic cell death by reversing a cancer-driven DNA methylation effect may lead to the development of novel adjunct therapies.

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Glucocorticoid receptor gene expression and promoter CpG modifications throughout the human brain

Cited by 35 publications

References 44 publications

Traumatic Stress and Human DNA Methylation: A Critical Review

Traumatic Stress and Human DNA Methylation: A Critical Review

Breed-specific expression of GR exon 1 mRNA variants and profile of GR promoter CpG methylation in the hippocampus of newborn piglets

The N‐terminal transactivation domain of the glucocorticoid receptor mediates apoptosis of human small cell lung cancer cells

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