DNA methylation

Covalent methyl-group modification of DNA, involved in regulation and cellular memory. Its relationship to transcription depends on genomic location and biological context.

5-Methylcytosine is a modified cytosine with a methyl group attached to carbon 5 of its ring. In DNA, it retains the usual pairing relationship with guanine, so DNA methylation can change the chemical information on a sequence without changing its ordinary C/G base-pair identity.

A chemical difference makes the mark experimentally readable. In conventional bisulfite sequencing, treatment converts unmethylated cytosine to a form read as thymine after amplification, while 5-Methylcytosine is relatively protected. Comparing the resulting sequences reveals methylation at individual positions. The method introduced by M. Frommer and colleagues in 1992 turned a modification invisible in a simple four-letter DNA string into a positional readout.^[ref] A methylation measurement must still be interpreted in its genomic and cellular context; the mark does not mean universal shutdown of transcription.

Methylation in an asymmetric CHH sequence context, where H is A, C or T; maintenance of the pattern requires repeated targeting rather than direct copying from a symmetric dyad.

Methylation in the CHG sequence context, where H is A, C or T; its restoration is strongly coupled to H3K9 methylation.

Methylation in the symmetric CG sequence context.

The symmetry matters after DNA replication: each daughter duplex can retain a methylated parental strand and an initially unmodified new strand. Maintenance DNA methylation can use that relationship to help restore the previous pattern, without changing the underlying base sequence. ^[ref]

Establishment of methylation at a site that lacks the previous methylation pattern; sequence-directed and chromatin-directed recruitment provide specificity.

Re-establishment of a pre-existing methylation pattern following DNA replication.

A daughter duplex can initially contain a modified parental strand paired with an unmodified new strand. A maintenance system restores the matching mark, whereas de novo methylation establishes marks at previously unmodified positions. These are different ways to preserve or alter an epigenetic pattern. ^[ref]

Loss of methylated cytosines through active enzymatic replacement or through failed maintenance during replication.

A plant DNA glycosylase involved in reproductive epigenetic reprogramming and maternal imprinting effects.

Removing modified cytosines through a repair-linked reaction can reset selected methylation states. Its developmental role depends on where and when the enzyme acts, connecting local chemical editing of DNA to differences in parental-allele expression. ^[ref]

A plant DNA glycosylase/lyase involved in active DNA demethylation through a repair-associated pathway.

Active replacement can counterbalance methylation-dependent silencing at selected loci. This differs from passive dilution of a mark during replication, because the modified base is enzymatically removed through a repair-linked pathway. ^[ref]

A DNA methyltransferase transfers a methyl group to DNA, commonly using S-adenosylmethionine as donor. Different enzymes modify different bases or sequence contexts. Some preserve an existing pattern after DNA replication, whereas others establish new marks. Consequently, unchanged sequence can coexist with altered DNA methylation and gene regulation; the modification changes chemical information on the inherited template rather than necessarily changing its base order. ^[ref]

A methyltransferase recruited by RNA-directed DNA methylation that can establish methylation in multiple cytosine sequence contexts.

A plant chromomethylase contributing strongly to CHH methylation in heterochromatic regions.

This complements other plant methylation systems that act preferentially in different sequence or chromatin contexts. Separating CHH methylation from symmetric CG or CHG contexts is important because the patterns have different maintenance requirements after replication. ^[ref]

A plant chromomethylase important for CHG methylation and its coupling to H3K9 methylation.

Recognition of chromatin state helps couple DNA methylation to histone methylation, reinforcing a locally repressive environment. This is an interaction between two kinds of molecular mark, rather than conversion of one mark into the other. ^[ref]

A plant CG methylation maintenance enzyme.

Its activity helps copy a CG methylation pattern after DNA replication. Reduced MET1 function can therefore change heritable chromatin states while leaving the corresponding DNA base order unchanged; this separates an epigenetic mark from a sequence mutation. ^[ref]

A genomic interval with a statistically supported difference in DNA methylation between the compared samples.

A posterior methylation profile gives the posterior probability of DNA methylation at each modeled site. It differs from one sampled binary pattern and from a maximum-probability joint pattern.

Bisulfite sequencing infers cytosine modification from differential chemical conversion before DNA sequencing. Under the relevant chemistry, unmodified cytosine is converted to uracil and is subsequently read as thymine, while 5-methylcytosine is retained as cytosine. Incomplete conversion, sequence coverage and strand assignment affect interpretation. Conventional bisulfite sequencing does not by itself separate 5-methylcytosine from every other conversion-resistant modification, so its signal requires a stated chemical scope. ^[ref]