Age and sun exposure-related widespread genomic blocks of hypomethylation in nonmalignant skin

BackgroundAging and sun exposure are the leading causes of skin cancer. It has been shown that epigenetic changes, such as DNA methylation, are well established mechanisms for cancer, and also have emerging roles in aging and common disease. Here, we directly ask whether DNA methylation is altered following skin aging and/or chronic sun exposure in humans.ResultsWe compare epidermis and dermis of both sun-protected and sun-exposed skin derived from younger subjects (under 35 years old) and older subjects (over 60 years old), using the Infinium HumanMethylation450 array and whole genome bisulfite sequencing. We observe large blocks of the genome that are hypomethylated in older, sun-exposed epidermal samples, with the degree of hypomethylation associated with clinical measures of photo-aging. We replicate these findings using whole genome bisulfite sequencing, comparing epidermis from an additional set of younger and older subjects. These blocks largely overlap known hypomethylated blocks in colon cancer and we observe that these same regions are similarly hypomethylated in squamous cell carcinoma samples.ConclusionsThese data implicate large scale epigenomic change in mediating the effects of environmental damage with photo-aging.

[1]  B. Langmead,et al.  BSmooth: from whole genome bisulfite sequencing reads to differentially methylated regions , 2012, Genome Biology.

[2]  Martin J Aryee,et al.  Differential methylation of tissue- and cancer-specific CpG island shores distinguishes human induced pluripotent stem cells, embryonic stem cells and fibroblasts , 2009, Nature Genetics.

[3]  Jun Yu,et al.  Transcriptome Analysis of Skin Photoaging in Chinese Females Reveals the Involvement of Skin Homeostasis and Metabolic Changes , 2013, PloS one.

[4]  S. Hoath,et al.  The organization of human epidermis: functional epidermal units and phi proportionality. , 2003, The Journal of investigative dermatology.

[5]  Gustavo F. Bayón,et al.  H3K4me1 marks DNA regions hypomethylated during aging in human stem and differentiated cells , 2015, Genome research.

[6]  J. Voorhees,et al.  Pathophysiology of premature skin aging induced by ultraviolet light. , 1997, The New England journal of medicine.

[7]  L. Wessels,et al.  Domain organization of human chromosomes revealed by mapping of nuclear lamina interactions , 2008, Nature.

[8]  Rafael A Irizarry,et al.  Frozen robust multiarray analysis (fRMA). , 2010, Biostatistics.

[9]  Wolfgang Wagner,et al.  Age-dependent DNA methylation of genes that are suppressed in stem cells is a hallmark of cancer. , 2010, Genome research.

[10]  B. Korn,et al.  Aging and Chronic Sun Exposure Cause Distinct Epigenetic Changes in Human Skin , 2010, PLoS genetics.

[11]  Arthur Rook,et al.  Rook's Textbook of Dermatology , 2004 .

[12]  Martin Renqiang Min,et al.  An integrated encyclopedia of DNA elements in the human genome , 2012 .

[13]  T. Ideker,et al.  Genome-wide methylation profiles reveal quantitative views of human aging rates. , 2013, Molecular cell.

[14]  R. Irizarry,et al.  A gene expression bar code for microarray data , 2007, Nature Methods.

[15]  Peter D. Adams,et al.  Senescent cells harbour features of the cancer epigenome , 2013, Nature Cell Biology.

[16]  J. McGrath,et al.  Anatomy and Organization of Human Skin , 2008 .

[17]  H. Takeuchi,et al.  Longwave UV light induces the aging-associated progerin. , 2013, The Journal of investigative dermatology.

[18]  A. Feinberg,et al.  Large-scale hypomethylated blocks associated with Epstein-Barr virus–induced B-cell immortalization , 2014, Genome research.

[19]  S. Suster,et al.  Diagnostic Utility and Comparative Immunohistochemical Analysis of MITF-1 and SOX10 to Distinguish Melanoma In Situ and Actinic Keratosis: A Clinicopathological and Immunohistochemical Study of 70 Cases , 2014, The American Journal of dermatopathology.

[20]  A. Feinberg,et al.  Genome-wide methylation analysis of human colon cancer reveals similar hypo- and hypermethylation at conserved tissue-specific CpG island shores , 2008, Nature Genetics.

[21]  Alfonso Valencia,et al.  Distinct DNA methylomes of newborns and centenarians , 2012, Proceedings of the National Academy of Sciences.

[22]  Paolo Vineis,et al.  Epigenome-wide association study in the European Prospective Investigation into Cancer and Nutrition (EPIC-Turin) identifies novel genetic loci associated with smoking. , 2013, Human molecular genetics.

[23]  Atif Shahab,et al.  Whole-genome mapping of histone H3 Lys4 and 27 trimethylations reveals distinct genomic compartments in human embryonic stem cells. , 2007, Cell stem cell.

[24]  A. Feinberg,et al.  Common DNA methylation alterations in multiple brain regions in autism , 2014, Molecular Psychiatry.

[25]  Mark I. McCarthy,et al.  Global analysis of DNA methylation variation in adipose tissue from twins reveals links to disease-associated variants in distal regulatory elements. , 2013, American journal of human genetics.

[26]  K. Gunderson,et al.  High density DNA methylation array with single CpG site resolution. , 2011, Genomics.

[27]  Irving L. Weissman,et al.  A comprehensive methylome map of lineage commitment from hematopoietic progenitors , 2010, Nature.

[28]  K. Lindberg,et al.  Enzymatic dissociation of keratinocytes from human skin biopsies for in vitro cell propagation , 1999, Experimental dermatology.

[29]  John D. Storey,et al.  Capturing Heterogeneity in Gene Expression Studies by Surrogate Variable Analysis , 2007, PLoS genetics.

[30]  J. Uitto,et al.  Intrinsic aging vs. photoaging: a comparative histopathological, immunohistochemical, and ultrastructural study of skin , 2002, Experimental dermatology.

[31]  Andrew E. Teschendorff,et al.  Age-associated epigenetic drift: implications, and a case of epigenetic thrift? , 2013, Human molecular genetics.

[32]  E. Andres Houseman,et al.  Reference-free cell mixture adjustments in analysis of DNA methylation data , 2014, Bioinform..

[33]  Lijing Yao,et al.  Global loss of DNA methylation uncovers intronic enhancers in genes showing expression changes , 2014, Genome Biology.

[34]  H. Mukhtar,et al.  Kinetics of UV Light–induced Cyclobutane Pyrimidine Dimers in Human Skin In Vivo: An Immunohistochemical Analysis of both Epidermis and Dermis , 2000, Photochemistry and photobiology.

[35]  S. Horvath DNA methylation age of human tissues and cell types , 2013, Genome Biology.

[36]  Martin J. Aryee,et al.  Personalized Epigenomic Signatures That Are Stable Over Time and Covary with Body Mass Index , 2010, Science Translational Medicine.

[37]  P. Laird,et al.  Regions of focal DNA hypermethylation and long-range hypomethylation in colorectal cancer coincide with nuclear lamina–associated domains , 2011, Nature Genetics.

[38]  Jeffrey T Leek,et al.  Bump hunting to identify differentially methylated regions in epigenetic epidemiology studies. , 2012, International journal of epidemiology.

[39]  C. Zouboulis,et al.  Clinical aspects and molecular diagnostics of skin aging. , 2011, Clinics in dermatology.

[40]  Thomas Meitinger,et al.  A genome-wide association study confirms APOE as the major gene influencing survival in long-lived individuals , 2011, Mechanisms of Ageing and Development.

[41]  G. K. Sandve,et al.  Age-Associated Hyper-Methylated Regions in the Human Brain Overlap with Bivalent Chromatin Domains , 2012, PloS one.

[42]  Pablo Tamayo,et al.  Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[43]  H. Williams A photonumeric scale for the assessment of cutaneous photodamage. , 1992, Archives of dermatology.

[44]  Y. Poumay,et al.  Basal detachment of the epidermis using dispase: tissue spatial organization and fate of integrin alpha 6 beta 4 and hemidesmosomes. , 1994, The Journal of investigative dermatology.

[45]  Steven L Salzberg,et al.  Fast gapped-read alignment with Bowtie 2 , 2012, Nature Methods.

[46]  J. Mesirov,et al.  GenePattern 2.0 , 2006, Nature Genetics.

[47]  Y. Poumay,et al.  Basal detachment of the epidermis using dispase : tissue spatial organization and fate of integrin α6β4 and hemidesmosomes , 1994 .

[48]  T. Spector,et al.  Epigenetic differences arise during the lifetime of monozygotic twins. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[49]  Gordon K Smyth,et al.  Statistical Applications in Genetics and Molecular Biology Linear Models and Empirical Bayes Methods for Assessing Differential Expression in Microarray Experiments , 2011 .

[50]  L. Kaderali,et al.  Aging is associated with highly defined epigenetic changes in the human epidermis , 2013, Epigenetics & Chromatin.

[51]  Data production leads,et al.  An integrated encyclopedia of DNA elements in the human genome , 2012 .

[52]  Linda Partridge,et al.  Ageing as a Risk Factor for Disease , 2012, Current Biology.

[53]  Y. Helfrich,et al.  Effect of smoking on aging of photoprotected skin: evidence gathered using a new photonumeric scale. , 2007, Archives of dermatology.

[54]  A. Feinberg,et al.  Increased methylation variation in epigenetic domains across cancer types , 2011, Nature Genetics.

[55]  B. Gilchrest,et al.  Effects of aging and chronic sun exposure on melanocytes in human skin. , 1979, The Journal of investigative dermatology.

[56]  Owen T McCann,et al.  Human aging-associated DNA hypermethylation occurs preferentially at bivalent chromatin domains. , 2010, Genome research.

[57]  R. Irizarry,et al.  Accounting for cellular heterogeneity is critical in epigenome-wide association studies , 2014, Genome Biology.

[58]  Martin J. Aryee,et al.  Epigenome-wide association studies without the need for cell-type composition , 2014, Nature Methods.

[59]  Rafael A. Irizarry,et al.  Minfi: a flexible and comprehensive Bioconductor package for the analysis of Infinium DNA methylation microarrays , 2014, Bioinform..

[60]  J. Voorhees,et al.  Molecular basis of sun-induced premature skin ageing and retinoid antagonism , 1996, Nature.

[61]  S. Young,et al.  Targeting Protein Prenylation in Progeria , 2013, Science Translational Medicine.

[62]  Luigi Ferrucci,et al.  GeMes, clusters of DNA methylation under genetic control, can inform genetic and epigenetic analysis of disease. , 2014, American journal of human genetics.