Characterization of glucocorticoid-induced loss of DNA methylation of the stress-response gene <i>Fkbp5</i> in neuronal cells

Cox, Olivia; Song, Ha Young; Garrison-Desany, Henri; Gadiwalla, Nuriya; Carey, Jenny L.; Menzies, Julia; Lee, Richard S.

doi:10.1080/15592294.2020.1864169

Cited by 9 publications

(12 citation statements)

References 54 publications

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“…An alternative would be the identification of surrogate DNA regions recapitulating this global information. One region could be represented by the FKBP5 gene locus, whose methylation and expression have been demonstrated to be modulated by glucocorticoids in different tissues (45)(46)(47)(48)(49)(50), with hypomethylation of the promoter region associated with increased gene expression. In this study, we also identified the FKBP5 promoter region methylation as strongly associated with glucocorticoid excess, and negatively correlated with FKBP5 gene expression.…”

Section: Discussionmentioning

confidence: 99%

Identification of glucocorticoid-related molecular signature by whole blood methylome analysis

Armignacco

Jouinot

Bouys

et al. 2022

European Journal of Endocrinology

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Objective: Cushing’s syndrome represents a state of excessive glucocorticoids related to glucocorticoid treatments or to endogenous hypercortisolism. Cushing’s syndrome is associated with high morbidity, with significant inter-individual variability. Likewise, adrenal insufficiency is a life-threatening condition of cortisol deprivation. Currently, hormone assays contribute to identify Cushing’s syndrome or adrenal insufficiency. However, no biomarker directly quantifies the biological glucocorticoid action. The aim of this study was to identify such markers. Design: We evaluated whole blood DNA methylome in 94 samples obtained from patients with different glucocorticoid states (Cushing’s syndrome, eucortisolism, adrenal insufficiency). We used an independent cohort of 91 samples for validation. Methods: Leukocyte DNA was obtained from whole blood samples. Methylome was determined using the Illumina methylation chip array (~850000 CpG sites). Both unsupervised (Principal Component Analysis) and supervised (Limma) methods were used to explore methylome profiles. A Lasso-penalized regression was used to select optimal discriminating features. Results: Whole blood methylation profile was able to discriminate samples by their glucocorticoid status: glucocorticoid excess was associated with DNA hypomethylation, recovering within months after Cushing’s syndrome correction. In Cushing’s syndrome, an enrichment in hypomethylated CpG sites was observed in the region of FKBP5 gene locus. A methylation predictor of glucocorticoid excess was built on a training cohort and validated on two independent cohorts. Potential CpG sites associated with the risk for specific complications, such as glucocorticoid-related hypertension or osteoporosis, were identified, needing now to be confirmed on independent cohorts. Conclusions: Whole blood DNA methylome is dynamically impacted by glucocorticoids. This biomarker could contribute to better assess glucocorticoid action beyond hormone assays.

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Section: Discussionmentioning

confidence: 99%

Identification of glucocorticoid-related molecular signature by whole blood methylome analysis

Armignacco

Jouinot

Bouys

et al. 2022

European Journal of Endocrinology

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“…Our assessment showed a high quality of the generated data across all investigated tissues (blood, frontal cortex and hippocampus). DNAm of regions in the Fkbp5 locus have been investigated before using the pyrosequencing method (Cox et al, 2021; Ewald et al, 2014; Lee et al, 2010; Sawamura et al, 2016); however, using the HAM‐TBS method, we not only significantly extended the evaluation of important, previously described regulatory regions of the gene but also explored DNAm in additional, potentially relevant CpGs that have not yet been investigated, including those within mapped GREs and CTCF‐binding sites. We used this method to also explore long‐lasting changes in DNAm at all of these CpGs in relationship to ELS exposure.…”

Section: Discussionmentioning

confidence: 99%

“…Several studies revealed that single nucleotide polymorphisms (SNPs) of the FKBP5 gene interact with early life stress (ELS) exposure to increase the risk for the development of various psychiatric disorders (Matosin et al, 2018). Ever since, there have been increasing efforts to unravel the exact mechanisms behind this interactive process (Criado‐Marrero et al, 2019, 2020; Klengel et al, 2013; Klengel & Binder, 2015), and data from humans and mice have already suggested the involvement of epigenetics (Cox et al, 2021; Klengel et al, 2013; Lee et al, 2010; Matosin et al, 2018; Wiechmann et al, 2019; Womersley et al, 2022; Zannas et al, 2016). Klengel and colleagues demonstrated that individuals carrying the risk allele of the rs1360780 SNP of the FKBP5 gene, who were also exposed to childhood trauma, showed a demethylation at cytosine‐phosphate‐guanine‐dinucleotides (CpGs) near GREs in intron 7, leading to an increased FKBP5 mRNA induction by GR (Klengel et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

“…To further investigate the biological mechanism underlying the suggested GxE process, it is highly important to make a broader characterisation of DNAm of CpG sites near GREs at the mouse Fkbp5 gene, particularly with respect to ELS exposure. Previous studies have described the relationship between pharmacological GR activation and DNAm changes in the mouse Fkbp5 gene in various tissues (Cox et al, 2021; Ewald et al, 2014; Lee et al, 2010; Sawamura et al, 2016). So far, glucocorticoid‐induced differential DNAm profiles were observed in intron 1 of the Fkbp5 locus in the blood and in intron 5 in brain regions such as the hippocampus and the medial prefrontal cortex (Cox et al, 2021; Lee et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

“…Previous studies have described the relationship between pharmacological GR activation and DNAm changes in the mouse Fkbp5 gene in various tissues (Cox et al, 2021; Ewald et al, 2014; Lee et al, 2010; Sawamura et al, 2016). So far, glucocorticoid‐induced differential DNAm profiles were observed in intron 1 of the Fkbp5 locus in the blood and in intron 5 in brain regions such as the hippocampus and the medial prefrontal cortex (Cox et al, 2021; Lee et al, 2010). However, none of these studies addressed the consequences of adverse early life exposures.…”

Section: Introductionmentioning

confidence: 99%

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Extensive evaluation of DNA methylation of functional elements in the murine Fkbp5 locus using high‐accuracy DNA methylation measurement via targeted bisulfite sequencing

Yusupov

Doeselaar

Röh

et al. 2023

Eur J of Neuroscience

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FKBP5 is an important stress‐regulatory gene implicated in stress‐related psychiatric diseases. Single nucleotide polymorphisms of the FKBP5 gene were shown to interact with early life stress to alter the glucocorticoid‐related stress response and moderate disease risk. Demethylation of cytosine‐phosphate‐guanine‐dinucleotides (CpGs) in regulatory glucocorticoid‐responsive elements was suggested to be the mediating epigenetic mechanism for long‐term stress effects, but studies on Fkbp5 DNA methylation (DNAm) in rodents are so far limited. We evaluated the applicability of high‐accuracy DNA methylation measurement via targeted bisulfite sequencing (HAM‐TBS), a next‐generation sequencing‐based technology, to allow a more in‐depth characterisation of the DNA methylation of the murine Fkbp5 locus in three different tissues (blood, frontal cortex and hippocampus). In this study, we not only increased the number of evaluated sites in previously described regulatory regions (in introns 1 and 5), but also extended the evaluation to novel, possibly relevant regulatory regions of the gene (in intron 8, the transcriptional start site, the proximal enhancer and CTCF‐binding sites within the 5'UTR). We here describe the assessment of HAM‐TBS assays for a panel of 157 CpGs with possible functional relevance in the murine Fkbp5 gene. DNAm profiles were tissue‐specific, with lesser differences between the two brain regions than between the brain and blood. Moreover, we identified DNAm changes in the Fkbp5 locus after early life stress exposure in the frontal cortex and blood. Our findings indicate that HAM‐TBS is a valuable tool for broader exploration of the DNAm of the murine Fkbp5 locus and its involvement in the stress response.

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Implementation of the Methyl-Seq platform to identify tissue- and sex-specific DNA methylation differences in the rat epigenome

Cox,

Seifuddin,

Guo

et al. 2024

Epigenetics

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Epigenomic annotations for the rat lag far behind those of human and mouse, despite the rat’s immense utility in pharmacological and behavioral studies and the need to understand their epigenetic mechanisms. We have designed a targeted-enrichment method followed by next-generation sequencing (Methyl-Seq) to identify DNA methylation (DNAm) signatures across the rat genome. The design reflected an attempt to create a more comprehensive investigation of the rat epigenome, as it included promoters, CpG islands, and island shores of all RefSeq genes. In this study, we implemented the rat Methyl-Seq platform and tested its ability to distinguish differentially methylated regions (DMRs) among three different tissue types, three distinct brain regions, and, in the hippocampus, between males and females. These comparisons yielded DNAm differences of differing magnitudes, many of which were independently validated by bisulfite pyrosequencing, including autosomal regions that were predicted to show the least degree of difference in DNAm between males and females. Quantitative reverse transcription PCR revealed that most genes associated with the DMRs showed tissue-, brain region-, and sex-specific differences in expression. In particular, we found evidence for sex-specific DNAm and expression differences at Tubb6 , Lrrn2 , Tex26 , and Sox5l1 , all of which play important roles in neurodevelopment and have been implicated in studies examining sex differences. Our results demonstrate the utility of the rat Methyl-Seq platform and suggest the presence of DNAm differences between the male and female hippocampus. The rat Methyl-Seq has the potential to provide epigenomic insights into pharmacological and behavioral studies performed in the rat.

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Characterization of glucocorticoid-induced loss of DNA methylation of the stress-response gene Fkbp5 in neuronal cells

Cited by 9 publications

References 54 publications

Identification of glucocorticoid-related molecular signature by whole blood methylome analysis

Identification of glucocorticoid-related molecular signature by whole blood methylome analysis

Extensive evaluation of DNA methylation of functional elements in the murine Fkbp5 locus using high‐accuracy DNA methylation measurement via targeted bisulfite sequencing

Implementation of the Methyl-Seq platform to identify tissue- and sex-specific DNA methylation differences in the rat epigenome

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