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Transcriptional Control of the Glucocorticoid Receptor: Cpg Islands, Epigenetics and More

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Transcriptional Control of the Glucocorticoid Receptor: Cpg Islands, Epigenetics and More Transcriptional control of the glucocorticoid receptor: CpG islands, epigenetics and more. Jonathan D. Turner, Simone R. Alt, Lei Cao, Sara Vernocchi, Slavena Trifonova, Nadia Battello, Claude P. Muller To cite this version: Jonathan D. Turner, Simone R. Alt, Lei Cao, Sara Vernocchi, Slavena Trifonova, et al.. Transcriptional control of the glucocorticoid receptor: CpG islands, epigenetics and more.. Biochemical Pharmacology, Elsevier, 2010, 80 (12), pp.1860. 10.1016/j.bcp.2010.06.037. hal-00637161 HAL Id: hal-00637161 https://hal.archives-ouvertes.fr/hal-00637161 Submitted on 31 Oct 2011 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Accepted Manuscript Title: Transcriptional control of the glucocorticoid receptor: CpG islands, epigenetics and more. Authors: Jonathan D. Turner, Simone R. Alt, Lei Cao, Sara Vernocchi, Slavena Trifonova, Nadia Battello, Claude P. Muller PII: S0006-2952(10)00471-5 DOI: doi:10.1016/j.bcp.2010.06.037 Reference: BCP 10618 To appear in: BCP Received date: 4-5-2010 Revised date: 18-6-2010 Accepted date: 21-6-2010 Please cite this article as: Turner JD, Alt SR, Cao L, Vernocchi S, Trifonova S, Battello N, Muller CP, Transcriptional control of the glucocorticoid receptor: CpG islands, epigenetics and more., Biochemical Pharmacology (2010), doi:10.1016/j.bcp.2010.06.037 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. 1 GR Transcription 2 3 4 5 1 Transcriptional control of the glucocorticoid receptor: CpG islands, epigenetics and more. 6 7 8 2 9 10 1,2 1,2 1,2 1,2 11 3 Jonathan D. Turner , Simone R. Alt , Lei Cao , Sara Vernocchi , Slavena 12 13 4 Trifonova1,2, Nadia Battello1, Claude P. Muller1,2 14 15 16 5 17 18 19 6 1Institute of Immunology, CRP-Santé / Laboratoire National de Santé, 20A rue Auguste 20 21 22 7 Lumière, L-1950, Luxembourg 23 24 25 8 2Department of Immunology, Graduate School of Psychobiology, University of 26 27 28 9 Trier, D-54290, Germany 29 30 10 31 32 33 11 34 35 36 12 37 38 39 13 Running title: GR transcription 40 41 42 14 43 44 45 15 46 47 48 16 Address for correspondence: 49 50 17 Claude P. Muller,Accepted Institute of Immunology, CRP -Santé/LaboratoireManuscript National de Santé, 51 52 18 20A rue Auguste Lumière, L-1950 Grand Duchy of Luxembourg. 53 19 Tel: +352 490604 Fax: +352 490686 54 55 20 Email: [email protected] 56 21 57 58 59 60 61 62 63 1 64 Page 1 of 32 65 1 GR Transcription 2 3 4 1 Abstract 5 6 2 The unique variability in the 5’ region of the GR gene, with 9 alternative first exons and 7 8 9 3 13 splice variants plays a critical role in transcriptional control maintaining homeostasis 10 11 4 of the glucocorticoid receptor (GR). This 5’mRNA heterogeneity, common to all species 12 13 5 investigated, remains untranslated since the alternative first exons are spliced to exon 2 14 15 16 6 immediately upstream of the translation initiation codon. These alternative first exons are 17 18 7 located either immediately upstream of the coding exons in the CpG island (exons B-H 19 20 21 8 and J), or further upstream (exons 1A and 1I). The mechanisms regulating the differential 22 23 9 usage of these first exons in different tissues and individuals, and the role of the 5’UTR 24 25 26 10 in the splicing of the coding exons are still poorly understood. Here we review some of 27 28 11 the mechanisms that have so far been identified. Data from our laboratory and others 29 30 12 have shown that the multiple first exons represent only a first layer of complexity 31 32 33 13 orchestrated probably by tissue-specific transcription factors. Modulation of alternative 34 35 14 first exon activity by epigenetic methylation of their promoters represents a second layer 36 37 38 15 of complexity at least partially controlled by perinatal programming. The alternative 39 40 16 promoter usage also appears to affect the 3’ splicing generating the different GR coding 41 42 43 17 variants, GR, GRβ, and GR-P. Aberrant GR levels are associated with stress-related 44 45 18 disorders such as depression, and affect social behaviour, mood, learning and memory. 46 47 48 19 Dissecting how tissue-specific GR levels are regulated, in particular in the brain, is a first 49 50 20 step to understandAccepted the significance of aberrant GRManuscript levels in disease and behaviour. 51 52 53 21 54 55 56 22 Keywords: Glucocorticoid receptor; Promoter; Methylation; Epigenetic variability; 57 58 23 alternative exon splicing 59 60 61 24 62 63 2 64 Page 2 of 32 65 1 GR Transcription 2 3 4 1 Introduction 5 6 7 2 Stress causes an increasing disease burden at least in Western societies. Economic losses 8 9 3 due to stress may be as high as 3-4% of the European gross national product. In addition, 10 11 12 4 stress has detrimental effects on behaviour, mood, learning and memory that are difficult 13 14 5 to quantify. Glucocorticoids (GCs), the key stress mediators, exert profound effects on a 15 16 6 wide range of physiological and developmental processes that are crucial for the 17 18 19 7 adaptation to stress. Psychosocial stress has also been implicated in the development of 20 21 8 mental disorders, including schizophrenia, anxiety disorders, and depression. 22 23 24 9 GCs act via binding to two types of intracellular nuclear receptors, i.e. the glucocorticoid 25 26 10 receptor (GR) and the mineralocorticoid receptor (MR). Upon binding of GCs, these 27 28 29 11 receptors translocate to the nucleus where they regulate the activity of specific target 30 31 12 genes, in a cell-type specific manner, as transcription factors. This review focuses on the 32 33 34 13 classical GR, NR3C1. Numerous factors have been demonstrated to affect the 35 36 14 responsiveness to GC by regulating GR activity, such as GR co-activators and co- 37 38 15 repressors [1], GR splice-variants [2-4], and GR isoforms [5-7]. In addition, and perhaps 39 40 41 16 most important for GC responsiveness is the expression level of GR protein [8-11], 42 43 17 determined by the mRNA level. 44 45 46 18 In eukaryotic cells, gene expression is controlled by a variety of mechanisms, both at 47 48 19 transcriptional and translational levels, including chromatin condensation, transcription 49 50 Accepted Manuscript 51 20 initiation, DNA methylation, alternative RNA splicing, mRNA stability and others. The 52 53 21 GR is an ubiquitously expressed nuclear hormone receptor, however, levels of both 54 55 22 mRNA and protein vary widely between cell and tissue types. Over the last few years we 56 57 58 23 and others have contributed to the significant progress that has been made to unravel the 59 60 61 62 63 3 64 Page 3 of 32 65 1 GR Transcription 2 3 4 1 transcriptional mechanisms determining the tissue specific control of GR levels, that will 5 6 7 2 be reviewed here. 8 9 3 10 11 12 4 Structure of the NR3C1 gene 13 14 5 The human GR gene (OMIM + 138040; NR3C1) is located on chromosome 5q31-q32 15 16 6 [12] and contains 8 translated exons (2-9) and 9 untranslated alternative first exons. We 17 18 19 7 and others have shown that GR levels are under the transcriptional control of a complex 20 21 8 5’ structure of the gene, containing the untranslated first exons important for differential 22 23 24 9 expression of the GR. All of the alternative first exons identified are located in one of the 25 26 10 two promoter regions: the proximal or the distal promoter region, located approximately 27 28 29 11 5kb and 30kb upstream of the translation start site, respectively [13-18]. Alternative first 30 31 12 exons 1A, and 1I are under the control of promoters in the distal promoter region, 32 33 34 13 whereas the promoters of exons 1D, 1J, 1E, 1B, 1F, 1C (1C1-3), 1H (Fig. 1A) are located 35 36 14 in the proximal promoter region [19, 20]. Exons 1D to 1H are found in an upstream CpG 37 38 15 island with a high sequence homology between rats and humans. 39 40 41 16 The region- or tissue-specific usage of alternative first exons leading to different GR 42 43 17 mRNA transcripts [19, 20] (Fig. 1 B) provides a mechanism for the local fine-tuning of 44 45 46 18 GR levels. Since the ATG start codon lies only in the common exon 2, this 5’mRNA 47 48 19 heterogeneity remains untranslated, but is important for translational regulation [21].
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