EPIGENETICS #1

Dec., 2012

IMPRINTING

• GENOME has 2 copies of each gene – one from mother, one from father

• IMPRINTING - For some genes, only the copy from the mother ever gets switched on, and for others, only the copy from the father.– IGF2 only made by father’s genes

• EPIGENOME is responsible • ABNORMAL IMPRINTING

– Beckwith-Wiedmann syndrome, a disorder associated with body overgrowth and increased risk of cancer

– Prader-Willi and Angelman syndromes, which are disorders associated with obesity and mental retardation.

EPIGENETIC PATHWAYS

WHY IMPORTANT• Individuals have single genome but multiple

epigenomes– Different in different cells and tissues – May change over lifetime– Involved in many types of disease

• Identical twins become different with age

EPIGENETICS

• Cancer– Hypomethylation (20-60% less) chromosome

instability + oncogene activation – Hypermethylation tumor suppressor genes silenced

• Aging DNA methylation • Environmental factors: heavy metals, pesticide,

folate and methionine deficiencies, smoking, cocaine

• Type-2 diabetes, obesity, infertility, cardiovascular, mental disorders, neurodevelopmental disorders

EPIGENETIC PATHWAYS

Four types• DNA methylation • Histone modification• Nucleosome remodeling• Non-coding RNA-mediated pathways

Intertwine to regulate expression of genes

TYPE 1: DNA Methylation

• CpG and CpG islands in linear DNA chain• Cytosine in CpG islands is methylated at 5th C• Methylation involved in regulating cell

differentiation and function• Too much or too little – Alters cell function – Results in disease

TYPE 2: Histone Modification

• Globular proteins; 4 main types but there are variants

• Histones exist as octamer– Pairs of histone H2A, H2B, H3 and H4– One/~147 bp of genomic DNA = nucleosome

• DNA + histone octamer = nucleosome = structural unit of chromatin

Histone Modification

• NH2 tails of histones post-translationally modified– Acetylated (acetyltransferases - HATs, deacetylases – HDACs)– Methylated (methytransferases, demethylases)– Phosphorylated (Kinases)– Ubiquinated

Above process = chromatin modification• Provides recruitment signals for nonhistone proteins (e.g.,

transcription factors)• Relaxes chromatin by disrupting contacts between

nucleosomes and interactions between histone tails and genomic DNA

• certain molecules are added to or removed from DNA, making it harder or easier for the DNA to be read and translated, and thus used to make proteins essential for cells to function

WATCH “A TAKE OF TWO MICE” http://www.pbs.org/wgbh/nova/body/epigenetics.html