Epigenetics
Figure 2 Crystal structure of the
nucleosome, the basic subunit of chromatin. DNA appears in light blue and histones are depicted as coloured helices. Post-translational
modifications of the histones are represented by black
‘lollipops’. Figure courtesy of Dr Karolin Luger, Colorado State University
H3
Ac
Me Me3
K Q Y R R I E R L A V T G 50
gave birth to healthy mice, in contrast to the moth- ers who did not receive this special diet. In a follow up study, the same pregnant agouti mice (Avy) were exposed to bisphenol A (BPA), a building block of polycarbonate plastics and epoxy resins used to make consumer goods ranging from water bottles to dental sealants7. BPA was found to significantly reduce DNA methylation in Avy mice by 31%, resulting in the birth of more obese, yel- low offspring who display a higher incidence of diabetes and cancer as adults. Although it remains to be demonstrated conclusively in humans, the use of the Avy agouti mouse as an epistable biosen- sor has proven to be a valuable animal model in demonstrating the influence of environmental exposure to modulation of gene expression and this particular study highlights a possible connec- tion between the increase in plastics in our envi- ronment and the rising incidence of obesity. Today, aberrant DNA hypermethylation is known to play a role in a number of diseases, including many types of cancer, which can result when tumour suppressor genes are subject to inap- propriate epigenetic inactivation8. Hypermethyla- tion is found in every type of human cancer and is the most well characterised epigenetic change to occur in tumours9.
P R P Y R H P Me Ac N
R A
K T
Me2
Me P
Ac Me Q T P A R K Ac
Me Me2 Me3
P Ub
Acetylation Methylation Dimethylation Trimethylation Phosphorylation Ubiquitination
10 Me2 S Me Ac P P Me2
T G G K A P R K Q L A T Ac
Me Ac Me2
Me 20
Me P
Me3 Me2 Me3 Me2 Me2 Ac K Me3 Me2 Me Me2 Me R A A P Ac K S A Me2 Me3 Me K K
V G G T
A P 30 40
There are two approaches to DNA methylation analysis. Typing technologies target a small num- ber of loci across many samples, and involve the use of techniques such as methylation-specific PCR (Figure 1), methylation-sensitive restriction enzymes and mass spectrometry. Genome-wide methylome profiling technologies, on the other hand, include bisulfite sequencing (unmethylated cytosine residues are converted to uracil), methy- lated DNA immunoprecipitation sequencing (MeDIP-Seq), methylated DNA capture by affinity purification sequencing (MethylCap-Seq) and methylation-sensitive restriction enzyme sequenc- ing (MRE-Seq). Advancements made in these map- ping technologies has made possible the large num- ber of recently published genome-wide methylome profiles in a wide variety of species and in the pres- ence of various environmental signals10. Current efforts are focused on sequencing the location of every methylated cytosine in an organism’s DNA, the ‘methylome’11. In addition, various DNA methyltransferase assays are available, allowing researchers to study the activity level of these enzymes in various species
Chromatin modifications Figure 3: Histone H3 modifications 28
Chromatin, a complex of DNA and associated pro- teins in the nucleus, is a higher ordered structure
Drug Discovery World Fall 2011
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