DNA methylation where does it occur?

CpG islands usually unmethylated

Intergenic regions usually methylated
Repetitive elements usually methylated

DNA methylation is mutagenic

CpGs under-represented in the genome
as methylated C is prone to deamination to T

H 3C

Cytosine

5-methyl Cytosine

Thymine

What is the function of DNA methylation at

intergenic regions?
Maintain genomic integrity?
Dnmt1 null cells display genomic instability
Silence cryptic transcription start sites or cryptic splice sites

What is the function of DNA methylation at

repetitive elements?
Maintain genomic integrity
silencing of repeats to prevent transposition
mutation of the repeats (meC to T) to prevent transposition
silencing of repeats, so avoid transcriptional interference from strong promoters
methylation of repeats may prevent illegitimate recombination

What is the function of DNA methylation at

repetitive elements?
Genome defense model (Prof. Timothy Bestor)
DNA methylation is mutagenic, so must also be a benefit i.e. protect the genome
from transposable elements

DNA methylation and cancer

In cancer, historically the earliest epigenetic aberration found was a genomewide lack of methylation,
- hypomethylation at intergenic regions/ repeats, and genomic instability
(covered in Cancer Epigenetics lectures later)

Feature found in all cancers ever studied, more consistently than genetic
mutations!

DNA demethylation

DNA methylation is mitotically heritable, and originally thought to be

irremovable, except by failure to maintain methylation by DNMT1

DNA demethylation shown to occur in early development, in primordial germ

cell development and at later specific stages of differentiation (covered in
Epigenetic Reprogramming lectures later)

Around year 2000, shown this could happen without DNA replication, so
could also be an active process

DNA demethylation how does it occur?

Passive DNA demethylation
- Dilution of DNA methylation with every cell division, when DNMT1 is not
expressed or not in the nucleus

Active DNA demethylation,

- Not simple removal of methyl group, as C-C bond is very difficult to remove
- Enzymatic removal via intermediates, using multiple different systems
- TET proteins main players, plus AID

Summary of DNA methylation

Occurs at CpG dinucleotides

Associated with gene silencing when found at promoters
Helps to maintain genomic stability
Laid down by DNA methyltransferases
Mitotically heritable, due to features of DNMT1
Can be removed passively, or actively which involves TET proteins
Essential for viability, as DNMT knockouts die in utero

Heritability of DNA methylation

Epigenetics is the study of mitotically heritable changes in gene expression that occur
without changes in DNA sequence.
DNA methylation is mitotically heritable because
1. DNMT1 recognises hemi-methylated DNA and
restores methylation on both strands

Heritability of DNA methylation

Epigenetics is the study of mitotically heritable changes in gene expression that occur
without changes in DNA sequence.
DNA methylation is mitotically heritable because
1. DNMT1 recognises hemi-methylated DNA and
restores methylation on both strands
2. TET proteins involved in active demethylation
are only expressed at very restricted times in
development