Profiles of Epigenetic Histone Post-translational Modifications at Type 1 Diabetes Susceptible Genes*

Background: Both genetic and epigenetic factors are implicated in Type 1 diabetes (T1D). Results: Variations in histone H3-lysine 9 acetylation are detected around the promoter/enhancer regions of key T1D susceptible genes in monocytes of T1D subjects versus normals. Conclusion: The chromatin status of this key region is altered in T1D. Significance: Epigenetic variations at T1D susceptible genes may be functionally important. Both genetic and environmental factors are implicated in type 1 diabetes (T1D). Because environmental factors can trigger epigenetic changes, we hypothesized that variations in histone post-translational modifications (PTMs) at the promoter/enhancer regions of T1D susceptible genes may be associated with T1D. We therefore evaluated histone PTM variations at known T1D susceptible genes in blood cells from T1D patients versus healthy nondiabetic controls, and explored their connections to T1D. We used the chromatin immunoprecipitation-linked to microarray approach to profile key histone PTMs, including H3-lysine 4 trimethylation (H3K4me3), H3K27me3, H3K9me3, H3K9 acetylation (H3K9Ac), and H4K16Ac at genes within the T1D susceptible loci in lymphocytes, and H3K4me3, H3K9me2, H3K9Ac, and H4K16Ac at the insulin-dependent diabetes mellitus 1 region in monocytes of T1D patients and healthy controls separately. We screened for potential variations in histone PTMs using computational methods to compare datasets from T1D and controls. Interestingly, we observed marked variations in H3K9Ac levels at the upstream regions of HLA-DRB1 and HLA-DQB1 within the insulin-dependent diabetes mellitus 1 locus in T1D monocytes relative to controls. Additional experiments with THP-1 monocytes demonstrated increased expression of HLA-DRB1 and HLA-DQB1 in response to interferon-γ and TNF-α treatment that were accompanied by changes in H3K9Ac at the same promoter regions as that seen in the patient monocytes. These results suggest that the H3K9Ac status of HLA-DRB1 and HLA-DQB1, two genes highly associated with T1D, may be relevant to their regulation and transcriptional response toward external stimuli. Thus, the promoter/enhancer architecture and chromatin status of key susceptible loci could be important determinants in their functional association to T1D susceptibility.

[1]  Jeffrey A. Bluestone,et al.  Genetics, pathogenesis and clinical interventions in type 1 diabetes , 2010, Nature.

[2]  J. Knight,et al.  The human Major Histocompatibility Complex as a paradigm in genomics research. , 2009, Briefings in functional genomics & proteomics.

[3]  M. Rewers,et al.  Multi-SNP Analysis of MHC Region Remarkable Conservation of HLA-A1-B8-DR3 Haplotype , 2006 .

[4]  Amanda J. Wilson,et al.  A search for type 1 diabetes susceptibility genes in families from the United Kingdom , 1998, Nature Genetics.

[5]  B. Chadwick,et al.  The insulator factor CTCF controls MHC class II gene expression and is required for the formation of long-distance chromatin interactions , 2008, The Journal of experimental medicine.

[6]  William Hagopian,et al.  Environmental factors in the development of Type 1 diabetes , 2007, Reviews in Endocrine and Metabolic Disorders.

[7]  Helen Schuilenburg,et al.  Genome-wide association study and meta-analysis finds over 40 loci affect risk of type 1 diabetes , 2009, Nature Genetics.

[8]  J. Nerup,et al.  HL-A antigens and diabetes mellitus. , 1974, Lancet.

[9]  M. Redondo,et al.  Genetics of type 1A diabetes. , 2001, Recent progress in hormone research.

[10]  P. Majumder,et al.  Regulation of major histocompatibility complex class II genes. , 2011, Current opinion in immunology.

[11]  R. A. Bailey,et al.  Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes , 2007, Nature Genetics.

[12]  Arne Svejgaard,et al.  HLA antigens and diabetes , 1980 .

[13]  L. Lanting,et al.  Epigenetic histone H3 lysine 9 methylation in metabolic memory and inflammatory phenotype of vascular smooth muscle cells in diabetes , 2008, Proceedings of the National Academy of Sciences.

[14]  J. Milne,et al.  An integrative approach , 1995 .

[15]  A. Visel,et al.  ChIP-seq accurately predicts tissue-specific activity of enhancers , 2009, Nature.

[16]  Mitsuo Kato,et al.  Epigenetic histone methylation modulates fibrotic gene expression. , 2010, Journal of the American Society of Nephrology : JASN.

[17]  John A. Todd,et al.  Genetics of Type 1 Diabetes: What's Next? , 2010, Diabetes.

[18]  M. Rewers,et al.  Extreme genetic risk for type 1A diabetes , 2006, Proceedings of the National Academy of Sciences.

[19]  Dustin E. Schones,et al.  High-Resolution Profiling of Histone Methylations in the Human Genome , 2007, Cell.

[20]  R. Roeder,et al.  Transient high glucose causes persistent epigenetic changes and altered gene expression during subsequent normoglycemia , 2008, The Journal of Experimental Medicine.

[21]  D. Reinberg,et al.  Transcription regulation by histone methylation: interplay between different covalent modifications of the core histone tails. , 2001, Genes & development.

[22]  C. Allis,et al.  The language of covalent histone modifications , 2000, Nature.

[23]  R. Steinman,et al.  Microbial Stimulation Fully Differentiates Monocytes to DC-SIGN/CD209+ Dendritic Cells for Immune T Cell Areas , 2010, Cell.

[24]  上田 裕紀.  Etiology of type 1 diabetes , 2011 .

[25]  P. Majumder,et al.  CTCF Controls Expression and Chromatin Architecture of the Human Major Histocompatibility Complex Class II Locus , 2010, Molecular and Cellular Biology.

[26]  Danny Reinberg,et al.  Histones: annotating chromatin. , 2009, Annual review of genetics.

[27]  R. Jirtle,et al.  Environmental epigenomics and disease susceptibility , 2007, Nature Reviews Genetics.

[28]  A. Klug,et al.  A low resolution structure for the histone core of the nucleosome , 1980, Nature.

[29]  W. Reith,et al.  CIITA is a transcriptional coactivator that is recruited to MHC class II promoters by multiple synergistic interactions with an enhanceosome complex. , 2000, Genes & development.

[30]  Ali Shilatifard,et al.  Chromatin modifications by methylation and ubiquitination: implications in the regulation of gene expression. , 2006, Annual review of biochemistry.

[31]  G. Hon,et al.  Next-generation genomics: an integrative approach , 2010, Nature Reviews Genetics.

[32]  J. Todd,et al.  A genome-wide search for human type 1 diabetes susceptibility genes , 1994, Nature.

[33]  S. Litherland.  Immunopathogenic Interaction of Environmental Triggers and Genetic Susceptibility in Diabetes , 2008, Diabetes.

[34]  H. Erlich,et al.  Genetics of type 1 diabetes. , 2012, Cold Spring Harbor perspectives in medicine.

[35]  J. Todd,et al.  HLA-DQβ gene contributes to susceptibility and resistance to insulin-dependent diabetes mellitus , 1987, Nature.

[36]  W. Reith,et al.  Chromatin remodeling and extragenic transcription at the MHC class II locus control region , 2003, Nature Immunology.

[37]  W. Fiers,et al.  Autocrine secretion of tumor necrosis factor under the influence of interferon-gamma amplifies HLA-DR gene induction in human monocytes. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[38]  Andrew Min,et al.  Lymphocytes From Patients With Type 1 Diabetes Display a Distinct Profile of Chromatin Histone H3 Lysine 9 Dimethylation , 2008, Diabetes.

[39]  Mark Bieda,et al.  Unbiased location analysis of E2F1-binding sites suggests a widespread role for E2F1 in the human genome. , 2006, Genome research.

[40]  J. Dausset.  The Major Histocompatibility Complex in Man , 1992 .

[41]  Adrian Bird,et al.  Perceptions of epigenetics , 2007, Nature.

[42]  John J. Wyrick,et al.  Genome-wide location and function of DNA binding proteins. , 2000, Science.

[43]  R. Tothill,et al.  Genome-wide analysis distinguishes hyperglycemia regulated epigenetic signatures of primary vascular cells. , 2011, Genome research.

[44]  A. Davoodi-Semiromi,et al.  GM-CSF induces STAT5 binding at epigenetic regulatory sites within the Csf2 promoter of non-obese diabetic (NOD) mouse myeloid cells. , 2008, Journal of autoimmunity.

[45]  A. Shilatifard,et al.  An operational definition of epigenetics. , 2009, Genes & development.

[46]  M. Rewers,et al.  Multi-SNP Analysis of MHC Region , 2006, Diabetes.

[47]  Jaakko Tuomilehto,et al.  Time trends in the incidence of type 1 diabetes in Finnish children: a cohort study , 2008, The Lancet.

[48]  R. Natarajan,et al.  The role of epigenetics in the pathology of diabetic complications. , 2010, American journal of physiology. Renal physiology.

[49]  D. Clayton,et al.  Genome-wide association study and meta-analysis finds over 40 loci affect risk of type 1 diabetes , 2009, Nature Genetics.

[50]  A. Shilatifard,et al.  The chromatin signaling pathway: diverse mechanisms of recruitment of histone-modifying enzymes and varied biological outcomes. , 2010, Molecular cell.

[51]  J. Todd.  Genetics of type 1 diabetes. , 1997, Pathologie-biologie.

[52]  M. Cooper,et al.  Hyperglycemia Induces a Dynamic Cooperativity of Histone Methylase and Demethylase Enzymes Associated With Gene-Activating Epigenetic Marks That Coexist on the Lysine Tail , 2008, Diabetes.

[53]  A. Riggs,et al.  Reduction of Raf Kinase Inhibitor Protein Expression by Bcr-Abl Contributes to Chronic Myelogenous Leukemia Proliferation* , 2009, Journal of Biological Chemistry.

[54]  Nathaniel D. Heintzman,et al.  Histone modifications at human enhancers reflect global cell-type-specific gene expression , 2009, Nature.

[55]  Rama Natarajan,et al.  In Vivo Chromatin Remodeling Events Leading to Inflammatory Gene Transcription under Diabetic Conditions* , 2004, Journal of Biological Chemistry.

[56]  G. Eisenbarth.  Banting Lecture 2009: An Unfinished Journey: Molecular Pathogenesis to Prevention of Type 1A Diabetes , 2010, Diabetes.