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The Importance of Epigenetic
Phenomena in Regulating Activity of
the Genetic Material
Sin Chan
Genetics
• Study of genes, heredity and variation
• Traditional focus for genetic analysis has been DNAcentric (DNA as blueprint for life)
Epigenetics
• Genes as destiny?
• Defined as the study of factors affecting gene expression,
but not the DNA sequence
– May be acquired, and not only inherited
• Jean-Baptiste Lamarck (1744-1829)
– French scientist
– Theory that acquired
traits/characteristics may be
passed on
• Mechanisms:
– Histone Modification
– DNA methylation
Histone Modification
• Histones
– Proteins
– Involved in DNA packaging
– H2A, H2B, H3, and H4
• Histone code hypothesis
– Genetic information is partly regulated by chemical
modifications to unstructured ends
• 5 kinds of histone modifications
– Acetylation, methylation, ubiquination, phosphorylation, and
sumoylation
Histone Acetylation
• Important role in gene regulation
• Acetylation and deactylation of lysine residues on Nterminus tail and histone core
• Reaction catalyzed by enzymes histone
acetyltransferases (HATs) and histone deacetylase
(HDAC)
• Acetylation removes positive charge on histone
– Causes N-terminus to loosely bind to negatively charged
DNA phosphate group
– Allows easier access to DNA for transcription factor
– Genes more readily expressed
• Acetylation reversed by HDAC
DNA Methylation
• Best understood epigenetic modification
• Methyl groups attach to backbone of genome
at CpG sequences
– Cytosine bases5-methylcytosine
• DNA methyltransferases (Dnmt)
• Represses gene expression
– Silences genes; (ex. - tumor suppressor genes)
Human Epigenome Project
• Epigenomics
– Study of chemical tags that control
activities of genes
• Human Epigenome Consortium
– Collaboration of public and private institutions
• Goal of project
– Identify, catalogue and interpret genome-wide
DNA methylation patterns
Bisulfite Sequencing
• identification of DNA methylation patterns
Behavior
• Environmental factors/adaptations passed on to
offspring
• Paternal Effects
– Environment experienced by paternal lineage can
indirectly affect descendants
– Ex.) Swedish community
• Shortage of food
• Malnutrition between 9-12 years old in grandfather
increased lifespan of grandchildren
• Adequate nutrition and food decreased lifespan
– Heart disease and diabetes
• Diet plays a part in methylation of DNA
Agouti Mouse
• Diet of mother shapes epigenome of offspring
• Unmethylated agouti gene leads to obesity
and more susceptible to cancer and diabetes
– Yellow coat color
• Normally agouti gene methylated
– Healthy and brown coat color
Agouti Mouse
• Experiment:
– Pregnant yellow mouse fed methyl rich diet
– Offspring brown and healthy, did not inherit
yellow coat color or susceptibility to disease
– Concluded health determined by environmental
factors of what our parents eat
Twinning Phenomenon
Stem Cells
• Two important properties
– Self renewal
– Pluripotency
• Pluripotency reduced over
time and cell division
• Epigenetic modifications
stabilize the lineage-specific
fate of cells
DNA Methylation of Stem Cells
• DNA methylation low in regions of DNA
sequence that are CpG rich (CpG islands) in
stem cells
• DNA methylation increase during lineagespecification of cells
– Methylation targeted at promoter regions
– Increase causes loss of pluripotency
Cancer
• Why study epigenetics in cancer?
– Prevention
– Detection
– Treatment
• Epigenetic effects:
– Silencing of tumor suppressor genes
– Activation of oncogenes (gene with potential to
cause cancer)
DNA Methylation & Cancer
• DNA methylation in normal cells
– CpG island before promoter region of gene is
unmethylated
• DNA methylation in tumor cells
– CpG island before promoter region of gene is
hypermethylated
Hypermethylation
• Basically, an over abundance of methylation at
CpG islands
• Hypermethylation causes silencing of genes
– Silencing of tumor suppressor genes
– Causes tumorigenesis (production and formation
of tumors)
Histone Modifications & Cancer
• Healthy and cancer cells differ in histone
modification profiles
• Cancer cells:
– Decrease monoacetylated and trimethylated H4
(one of four types of histones involved in DNA
packaging)
– Decrease of acetylation on H3 and trimethylation
of H3 Lysine 4 (H3K4me3)
• Silence tumor suppressor gene, although there’s noted
demethylation of CpG islands
Controlling Epigenetic Modifications in
Cancer Cells
• DNA methylation inhibitor 5-aza-2’-deoxycytidine
– Prevents methylation of CpG islands
– Inhibits all three DNA methyltransferases (Dnmt1,
Dnmt3a, Dnmt3b)
– In clinical trials, proven to be effective in low dosage
and increasing survival rates
• Histone deacetylase inhibitors
– Problem: deacetylase proteins other than target
histones
Epigenetics
• Alter the way we view DNA expression
• Major role in:
– Behavior
– Stem Cell and Development
– Disease