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Review
. 2011 May 17;123(19):2145-56.
doi: 10.1161/CIRCULATIONAHA.110.956839.

Epigenetic modifications: basic mechanisms and role in cardiovascular disease

Diane E Handy  1 , Rita Castro, Joseph Loscalzo
Affiliations
Review

Epigenetic modifications: basic mechanisms and role in cardiovascular disease

Diane E Handy et al. Circulation. .
No abstract available

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Conflict of interest statement

Disclosures

The authors have no conflicts of interest to disclose.

Figures

Figure 1
Figure 1. Epigenetic tags and chromatin structure
Chromosomal DNA is packaged around histone cores to form nucleosomes. Nucleosome spacing in open structure that is accessible to nuclear factors is maintained, in part, by post-translational modification of histone tails, including lysine acetylation and specific lysine methylation. CpG dinucleotides are unequally distributed throughout chromosomal DNA, and may be concentrated in regions called CpG islands that can overlap gene promoters. Methylation of cytosines in CpG dinucleotides is overall associated with inactive, condensed states of the chromosome. Inactive chromatin is also maintained by specific histone lysine modifications.
Figure 2
Figure 2. DNA methylaton and demethylation
DNA methylation at the cytosine in CpG dinucleotides is initiated de novo by the DNA methyl transferases (DNMT) 3A and 3B. Following replication, DNMT1 plays a primary role in maintaining the methylation state in the daughter strands. Demethylation is thought to occur by reduction of DNMT1 activity or by excision repair mechanisms following deamidation of methyl cytosine (meC) to create a T:G mismatch. Recent findings (discussed further in the text) suggest that the methyl-DNA binding protein 4 (MBD4) may mediate demethylation by an hormonally regulated mechanism that does not involve deamination of meC, rather it involves the DNA glycosylase activity of MBD4 followed by a base-excision repair mechanism.
Figure 3
Figure 3. Homocysteine and methylation reactions
S-adenosyl-methionine (AdoMet) is the primary source of methyl groups for hundreds of transmethylases that methylate DNA, RNA, histones, other proteins, and small biological molecules. Following transfer of methyl groups, S-adenosyl-homocysteine (AdoHcy) is formed. Accumulation of AdoHcy can inhibit methyltranferases. The hydrolysis of AdoHcy yields homocysteine (Hcy) and adenosine. Intracellular homocysteine can be removed from the cell, reform AdoHcy, become further metabolized in the transsulfuration pathways (not illustrated), or become methylated to form methionine by the folate-dependent methionine synthase or the folate-independent betaine-Hcy methyltransferase.
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