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14

The Nature of Living Things

DNA Methylation

The enzymatic addition of methyl groups to cytosines prevents the gene from being

transcribed. This inactivation can be reversed (demethylation), but some genes are

irreversibly (permanently) inactivated (e.g., in the course of development), for exam-

ple, by destruction of the start site. It is not well understood how these different

degrees of inactivation come about. The interrelationship between histone modifica-

tion (Sect. 14.4.4) and DNA methylation may well play a rôle.

Methylation—of 5 prime5^'-C-G-3 prime3^' pairs (CpG; see Fig. 15.3)—is considered to be the

major epigenetic mechanism at the molecular level. ⁵³ The actual pattern of methy-

lation is highly specific according to the cell type. In 98% of the human genome,

CpGs occur roughly once per 80 base pairs but, in the remainder, one finds CpG

“islands”—sequences ranging from a few hundred to several thousand base pairs

with a roughly fivefold abundance of CpGs. These islands almost always encompass

gene promoters or exons; about half of all genes seem to contain such an island.

CpGs within islands are normally unmethylated, whereas most of those without the

islands are methylated (and hence transcriptionally inactive). ⁵⁴ Methylation is a way

of retaining information (gathered by the organism from its environment and from

its own functioning) at the ontogenic level.

Chromatin Conformation and Modification

Long regarded as passive structural elements (despite the fact that the chromosome

was known to undergo striking changes in compaction during mitosis), the histones

(Sect. 14.4.4) are now perceived as actively participating in the regulation of gene

expression. The essential principle is that the histones can be modified and unmodi-

fied by the covalent attachment and detachment of chemical groups, especially to and

from the protein “tails” that protrude from the more compact core of the nucleosome.

These result in changes in the protein conformation, affecting the conformation of

the DNA associated with the histone and affecting the affinity and accessibility to

RNAp. Acetyl groups have attracted particular attention, but methyl and phosphate

groups and even other proteins also appear to be involved. The effect of these mod-

ifications is to control whether the associated gene is expressed. The modifications

are catalysed by enzymes.

Currently, there are several ambiguities in the perception of nucleosome-modified

gene expression regulation; for example, either acetylation or deacetylation may

be required for enabling transcription and the modification can be local or global

(affecting an entire chromosome). Are the effects of the modifications on the ability of

transcription enzymes to bind and function at the DNA dependent on the modification

53 The conventional view is that mammalian methylation occurs exclusively, or at least predomi-

nantly, at CpGs, but see, e.g., Doerfler et al. (1990) and Guo et al. (2014).

54 Useful references for this section are Doerfler et al. (1990), Ramsahoye et al. (2000), and Bird

(2002).