13 - Epigenetics

Epigenetic mechanisms

Change in gene expression without altering DNA sequence

Methylation

• CpG islands - unmethylated CpGI’s in promoters allow transcription, methylated silence genes

• DNMT1 methylates the new strand after replication

• 5-aza-cytosine - drug used in cancer therapy, incorporated into DNA, blocks methylation, reactivates silences genes

Histone modifications

• Nucleosome - 147bp wrapped around histone actamer

• Acetylation - neutralises histone charge, reduces DNA binding and relaxes chromatin

• H3K4me - active genes

• H3K27me - represses

Genomic imprinting

• Parent specific gene expression, only maternal or paternal allele active

• Prader willi and angelman syndrome - chromosome 15

• Methylation silences one allele, antisense RNA blocks transcription, insulator protein blocks enhancers

X chromosome inactivation

• Used for dosage compensation in females, random

• XIST RNA coats one X, recruits silencing complexes, forms barr body (inactive chromosome)

• 15% of genes will remain active

Epigenetics in disease

• Cancer - hypermethylation silences tumour suppressors

• IVF may distrupt imprinting

• Maternal diet affects offspring epigentics- normally produce altering yellow and black pigment (yellow on during hair growth), jumping gene inserts near agouti gene, yellow permanently on

• Diet rich in B12 and folate (methyl donors) prevents