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Pathways of DNA Demethylation

  • Wendy Dean
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 945)

Abstract

The regulation of the genome relies on the epigenome to instruct, define and restrict the activities of growth and development. Among the cohort of epigenetic instructions, DNA methylation is perhaps the best understood. In most mammals, cycles of the addition and removal of DNA methylation constitute phases of reprogramming when the developing embryo must negotiate lineage defining and developmental commitment events. In these instances, the DNA methylation instruction is often removed, thereby allowing a change in permission for future development and a return to a more plastic and pluripotent state. Because of this, the germ line, upon demethylation, can give rise to gametes that are fully functional across generations and poised for totipotency. This return to a less differentiated state can also be achieved experimentally. The loss of DNA methylation constitutes one of the significant barriers to induced pluripotency and is a prerequisite for the generation of iPS cells. Taking fully differentiated cells, such as skin cells, and turning back the developmental clock heralded a technological breakthrough discovery in 2006 (Takahashi and Yamanaka 2006) with unprecedented promise in regenerative medicine. In this chapter, the mechanistic possibilities for DNA demethylation will be described in the context of natural and experimentally induced epigenetic reprogramming. The balance of the maintenance of this heritable mark together with its timely removal is essential for lifelong health and may be a key in our understanding of ageing.

Keywords

Active demethylation Passive demethylation Deamination Dnmt1 Uhfr1 

Abbreviations

5caC

5-Carboxylcytosine

5fC

5-Formylcytosine

5hmC

5-Hydroxymethylcytosine

5mC

5-Methylcytosine

A

Adenosine

AID

Activation-induced deaminase

AICDA

Activation-induced cytosine deaminase

Ape1

Apurinic/apyrimidinic (AP) endonuclease 1

APOBEC

Apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like

BER

Base excision repair

C

Cytosine

CpA

Cytosine–adenosine dinucleotide

CpG

Cytosine–guanosine dinucleotide

CGI

CpG islands

CXXC

Zinc finger protein-binding domain to non-methylated CpG

CHH

Asymmetric DNA methylation

DNA

Deoxyribonucleic acid

ES cells

Embryonic stem cells

DNMTs

DNA methyltransferases, Dnmt1, DNA (cytosine-5)-methyltransferase 1; Dnmt1o, DNA (cytosine-5)-methyltransferase 1 oocyte form; Dnmt1s, DNA (cytosine-5)-methyltransferase 1 somatic form; Dnmt3a, DNA (cytosine-5)-methyltransferase 3a

Dnmt3b

DNA (cytosine-5)-methyltransferase 3b

Dnmt3L

DNA (cytosine-5)-methyltransferase 3-like, E6.5, embryonic day 6.5

E13.5

Embryonic day thirteen

EGFP

Enhanced green fluorescent protein

ELP1

Elongator complex protein 1

ELP3

Elongator complex protein 3

ELP4

Elongator complex protein 4

GV

Germinal vesicle

GVOs

Germinal vesicle oocytes

GSE

Gonad-specific expression

G

Guanosine

IAP

Intracisternal A particles, IF, immunofluorescence

iPS cells

Induced pluripotent stem cells

H3K9me2

Histone H3 lysine 9 dimethylation

KO

Knockout, MBD2, methyl-CpG-binding domain 2

MBD4

Methyl-CpG-binding domain 4

NGS

Next-generation sequencing

NER

Nucleotide excision repair

Np95

Nuclear protein 95

RFTD

Replication foci targeting domain

PARP1

Poly-ADP-ribose polymerase 1

PRC2

Polycomb repressive complex

PGCs

Primordial germ cells

RRBS

Reduced representational bisulphite sequencing

RNA

Ribonucleic acid

RNAi

RNA interference

SAM

S-Adenosyl-L-methionine

siRNA

Small interfering RNA

SMUG1

Single-strand selective monofunctional uracil DNA glycosylase 1

SNT

Somatic nuclear transfer

T

Thymine

TDG

Thymine DNA glycosylase

TET1–3

Ten-eleven translocation 1, 2 or 3

U

Uracil

UNG2, ZGA

Zygotic genome activation

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Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Epigenetics Programme, The Babraham InstituteCambridgeUK

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