PI - Immune Endocrine Epigenetics Research Group
Deputy Head, Allergology, Immunology, Inflammation Research Unit
Department of Infection and Immunity,
Luxembourg institute of Health
Esch-sur-Alzette
Grand Duchy of Luxembourg
 | jonathan.turner@lih.lu |
Stress represents the single most important cause of disease, causing costs as high as 3-4 % of the European GNP, and up to 60% of all work-days lost to disease. Many of these diseases are related to infections and aberrant immune reactions. Our interest is in elucidating genetic, epigenetic, transcriptional, translation and post-translational mechanisms underlying environmental control of the stress reaction, and to understand how this contributes to the environmental control of phenotype development.
In particular, aberrant glucocorticoid receptor (GR) levels are associated with stress-related disorders such as depression, and affect social behaviour, mood, learning and memory. Dissecting how tissue-specific GR levels are regulated, in particular in the brain, is the first step towards understanding the mechanisms underlying aberrant GR levels in disease and altered behaviour. Over the last few years we have shown that the unique variability in the 5’ region of the GR gene, with 9 alternative first exons and 13 splice variants plays a critical role in transcriptional control maintaining homeostasis of the glucocorticoid receptor (GR). This 5’mRNA heterogeneity, common to all species investigated, remains untranslated since the alternative first exons are spliced to exon 2 immediately upstream of the translation initiation codon. These alternative first exons are located either immediately upstream of the coding exons in the CpG island (exons B-H and J), or further upstream (exons 1A and 1I). The mechanisms regulating the differential usage of these first exons in different tissues and individuals, and the role of the 5’UTR in the splicing of the coding exons are still poorly understood. Data from our laboratory and others have shown that the multiple first exons represent only a first layer of complexity orchestrated probably by tissue-specific transcription factors. The alternative promoter usage also appears to affect the 3’ splicing generating the different GR coding variants, GRalpha, GRbeta, and GR-P. We have also demonstrated the effects of reduced GR levels, and an altered HPA axis in circulating lymphocytes in stress related disorders (e.g. fibromyalgia patients) on GR target gene expression, cytokine regulation and levels of adhesion molecules.
Such molecular biology based studies do not take into account molecular mechanisms linking the environment to gene expression. These epigenetic mechanisms are extensive and complex and represent key mechanisms of adaptation. Central to our understanding is that these epigenetic mechanisms program transcription by modifying access to the DNA sequences. We are particularly interested in DNA methylation, a modification which occurs directly on the genomic DNA. Since the initial report of DNA methylation controlling both GR levels and HPA axis reactivity in the rat, we have shown that each of the GR alternative untranslated first exons has its own functional promoter that is sensitive to DNA methylation. Methylation levels and patterns within these promoters are stochastic and unique between individuals. Within these promoters the majority of evolutionarily conserved, and confirmed active transcription factor binding sites contain methylatable CpG sites, suggesting that methylation helps control GR expression in a tissue specific manner. As well as DNA methylation on specific gene promoters, we have available within our group two techniques for investigating genome-wide DNA methylation levels, MeDIP-Seq, and Methyl-Seq.
Current projects within the group are:
EpiPath - Epigenetic effects of early life adverse events on adult pathology
GoodSyn - with Dr Jacques Zimmer, epigenetics in Good Syndrome
MetCOEPs - DNA Methylation: conducting the orchestra from exposure to phenotype?
MADAM - MAternal Diabetes and neuropsychiAtric vulnerability in offspring: role of DNA methylation
In particular, aberrant glucocorticoid receptor (GR) levels are associated with stress-related disorders such as depression, and affect social behaviour, mood, learning and memory. Dissecting how tissue-specific GR levels are regulated, in particular in the brain, is the first step towards understanding the mechanisms underlying aberrant GR levels in disease and altered behaviour. Over the last few years we have shown that the unique variability in the 5’ region of the GR gene, with 9 alternative first exons and 13 splice variants plays a critical role in transcriptional control maintaining homeostasis of the glucocorticoid receptor (GR). This 5’mRNA heterogeneity, common to all species investigated, remains untranslated since the alternative first exons are spliced to exon 2 immediately upstream of the translation initiation codon. These alternative first exons are located either immediately upstream of the coding exons in the CpG island (exons B-H and J), or further upstream (exons 1A and 1I). The mechanisms regulating the differential usage of these first exons in different tissues and individuals, and the role of the 5’UTR in the splicing of the coding exons are still poorly understood. Data from our laboratory and others have shown that the multiple first exons represent only a first layer of complexity orchestrated probably by tissue-specific transcription factors. The alternative promoter usage also appears to affect the 3’ splicing generating the different GR coding variants, GRalpha, GRbeta, and GR-P. We have also demonstrated the effects of reduced GR levels, and an altered HPA axis in circulating lymphocytes in stress related disorders (e.g. fibromyalgia patients) on GR target gene expression, cytokine regulation and levels of adhesion molecules.
Such molecular biology based studies do not take into account molecular mechanisms linking the environment to gene expression. These epigenetic mechanisms are extensive and complex and represent key mechanisms of adaptation. Central to our understanding is that these epigenetic mechanisms program transcription by modifying access to the DNA sequences. We are particularly interested in DNA methylation, a modification which occurs directly on the genomic DNA. Since the initial report of DNA methylation controlling both GR levels and HPA axis reactivity in the rat, we have shown that each of the GR alternative untranslated first exons has its own functional promoter that is sensitive to DNA methylation. Methylation levels and patterns within these promoters are stochastic and unique between individuals. Within these promoters the majority of evolutionarily conserved, and confirmed active transcription factor binding sites contain methylatable CpG sites, suggesting that methylation helps control GR expression in a tissue specific manner. As well as DNA methylation on specific gene promoters, we have available within our group two techniques for investigating genome-wide DNA methylation levels, MeDIP-Seq, and Methyl-Seq.
Current projects within the group are:
EpiPath - Epigenetic effects of early life adverse events on adult pathology
GoodSyn - with Dr Jacques Zimmer, epigenetics in Good Syndrome
MetCOEPs - DNA Methylation: conducting the orchestra from exposure to phenotype?
MADAM - MAternal Diabetes and neuropsychiAtric vulnerability in offspring: role of DNA methylation
