Epigenomics and Aging How epigenetic regulation of gene expression is related to getting older What is epigenomics Study of heritable changes in phenotype or gene expression caused by mechanisms other than changes in DNA sequence Affects which genes are transcribed Reason for cell differentiation Main components are DNA methylation and histone modifications Image Copyright Dr Mark Hill 2009 Methylation Addition of a methyl group to the 5 position of cytosine in a cytosineguanine basepair CpG Inheritable passed to cells through replication Suppresses gene expression by Free Image Molecular Bio Web Bank 1 physically impeding transcription proteins or 2 recruiting other CpG binding proteins that change histone structure Occurs in 60 90 of genes Is not found in CpG islands regions of high unmethylated CpG concentration in promoters of housekeeping genes Can regulate genes throughout life Histone Modification Histones Act as spools around which DNA winds allowing DNA to condense into chromatin Undergo post translational modifications that regulate genes ie Methylation acetylation etc Chromatin Complex of DNA and histone proteins that make up chromosomes Comes in two varieties Heterochromatin condensed and generally inactive unexpressed Euchromatin uncondensed transcriptionally active Image borrowed from Richard Twyman the Wellcome Trust Epigenetics Changes over Lifetime Monozygotic twins despite being genetically identical diverge phenotypically over time Overall decrease in methylation as humans age more genes are on Abnormal methylation predominantly occurs at repetitive sequences meaning herterochromatin are affected most inactive genes become active At specific sites there is a tendency for DNA that was not methylated to become hypermethylated Occurs in CpG islands which are regulatory genes Significant methylation alterations found in Other epigenetic signalling genes LAMB 1 involved in subchromosomal domain positioning Genes involved in making enzymes like DNA methyltransferases Telomere maintenance gene loci TERT ERCC1 RAD50 The Werner gene loci involved in premature aging syndrome Related to DNA maintenance and repair as well as replication What causes these changes Genetics Familial clustering of methylation changes suggest inheritable methylation stability Environmental Exposures Inflammation carcinogens and diet are known to cause methylation alterations Tobacco alcohol arsenic and asbestos are associated with methylation induced gene inactivation Ex Caloric restriction affects longevity and preproorexin gene expression in mice Hunger Winter affected the insulin like growth factor 2 in children Hypermethylation of tumor suppressor genes in lung tissue of smokers Random Biological Variability Consequence 1 Senescence Aging the loss of corporal functions accompanied by a general degeneration of cells and tissues Accumulated chromatin damage and cell stress cause increased apoptosis Tissues do not renew themselves as normal because Decreased DNA methylation and deheterochromatinization contribute to faulty chromosome segregation and age associated aneuploidy Senescent cells become stuck in proliferation arrest Excessive number of cell divisions lead to shortening of telomeres Specialized forms of heterochromatin called Senescence Associated Heterochromain Foci SAHF silence expression of proliferation promoting genes which contributes to proliferation arrest ex baboon skin Leads to gradual deterioration in cell and tissue function with age Explains symptoms like cataracts loss of bone density loss of muscle mass and strength wrinkles in skin etc Overall progressive decay of adult stem cells potential to maintain tissular homeostasis Image from www beauty analysis com Consequence 2 Disease Susceptibility As we age we become more susceptible to diseases largely due to changes in epigenetics Cancer Involves both hypomethylation and hypermethylation Oncogenes prevent apoptosis and instead cause cells to survive and proliferate causing tumors activated Tumor suppressor genes promote apoptosis or repression of the cell cyce silenced Normally these genes work in conjunction to maintain healthy homeostatis of cells in tissues but alterations in their normal expression can lead to cancer Autoimmune diseases Autoreactivity genes cause cells that react against the organism of which they are part activated Histocompatibility genes determine immune tolerance to self silenced Disruption of gene expression causes immune system to start working against rather than for an organism Why haven t we learned Why haven t people evolved to live longer Disadvantages of aging occur after reproduction Natural selection could propagate a lethal or harmful gene as long as it appears after reproduction which is the case in most cancers and chronic diseases Antagonistic pleiotropy Some genes cause both increased reproduction in early life and aging in later life so senescence could be adaptive in evolution Ex Follicle depletion in human females causes both more regular cycles in early life and loss of fertility later in life through menopause Image by John Sedivy Brown University A more detailed example Sir2 in Yeast In S cerevisiae a type of yeast Sir 2 is an enzyme that removes the acetyl group from histones with the help of cofactor NAD Heterochromatinization prevents a sequence of repeats from dividing This is important as these repeats are normally prone to recombination to form extrachromosomal rDNA circles ERCs which curtail yeast lifespan By preventing transcription Sir2 stops these circles from not forming extending the life cycle of yeast Links cell metabolism genomic silencing and aging The Future Unanswered questions Which genomic sequences undergo DNA hypermethylation or hypomethylation events in aging cells Why these Is there any particular histone code for an aged cell What are the mechanisms by which epigenetic changes occur Do the epigenetic phenomena of aging apply in the same manner to all cell types in an organism Does a cell deficient in a DNA methylation or histone modifier gene show a characteristic disrupted aging status Are there epigenetic drugs that by changing DNA methylation and histone modification patterns could accelerate or slow the aging process Scientists hope to develop DNA methylome and a histone modification map that will help to define a young versus an old cell and to characterize all the chromatin modifier enzymes involved in the process but first we must understand
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