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Genetic Studies on Mammalian DNA Methyltransferases

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DNA Methyltransferases - Role and Function

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 945))

Abstract

Cytosine methylation at the C5-position, generating 5-methylcytosine (5mC), is a DNA modification found in many eukaryotic organisms, including fungi, plants, invertebrates, and vertebrates, albeit its levels vary greatly in different organisms. In mammals, cytosine methylation occurs predominantly in the context of CpG dinucleotides, with the majority (60–80 %) of CpG sites in their genomes being methylated. DNA methylation plays crucial roles in the regulation of chromatin structure and gene expression and is essential for mammalian development. Aberrant changes in DNA methylation levels and patterns are associated with various human diseases, including cancer and developmental disorders. DNA methylation is mediated by three active DNA methyltransferases (Dnmts), namely, Dnmt1, Dnmt3a, and Dnmt3b, in mammals. Over the last two decades, genetic manipulations of these enzymes, as well as their regulators, in mice have greatly contributed to our understanding of the biological functions of DNA methylation in mammals. In this chapter, we discuss genetic studies on mammalian Dnmts, focusing on their roles in embryogenesis, cellular differentiation, genomic imprinting, and X-chromosome inactivation.

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Abbreviations

5caC:

5-Carboxylcytosine

5fC:

5-Formylcytosine

5hmC:

5-Hydroxymethylcytosine

5mC:

5-Methylcytosine

ADCA-DN:

Autosomal dominant cerebellar ataxia deafness and narcolepsy

ADD:

ATRX-Dnmt3-Dnmt3L

AML:

Acute myeloid leukemia

BAH:

Bromo-adjacent homology

DKO:

Double knockout

DMR:

Differentially methylated region

DNMT:

DNA methyltransferase

ES:

Embryonic stem

EST:

Expressed sequence tag

HP1:

Heterochromatin protein 1

HSAN IE:

Hereditary sensory and autonomic neuropathy with dementia and hearing loss type IE

ICF:

Immunodeficiency centromeric instability and facial anomalies

ICM:

Inner cell mass

ICR:

Imprinting control region

KAP1:

KRAB-associated protein 1

KRAB:

Krüppel-associated box

lncRNA:

Long non-coding RNA

MBD3:

Methyl CpG-binding domain protein-3

MEF:

Mouse embryonic fibroblast

MTA2:

Metastasis tumor antigen 2

NLS:

Nuclear localization signal

NuRD:

Nuclear remodeling and histone deacetylation

PBD:

PCNA-binding domain

PCNA:

Proliferating cell nuclear antigen

PGC:

Primordial germ cell

PHD:

Plant homeodomain

PRC2:

Polycomb repressive complex 2

PWWP:

Proline-tryptophan-tryptophan-proline

RFTS:

Replication foci-targeting sequence

RING:

Really Interesting New Gene

SRA:

SET- and RING-associated

TDG:

Thymine DNA glycosylase

TTD:

Tandem tudor domain

UBL:

Ubiquitin-like

Uhrf1:

Ubiquitin-like with PHD and RING finger domains 1

Xa:

Active X chromosome

XCI:

X-chromosome inactivation

Xi:

Inactive X chromosome

Xic :

X-inactivation center

Xist :

X-inactive-specific transcript

Xm:

Maternal X chromosome

Xp:

Paternal X chromosome

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Acknowledgments

Work in the Chen laboratory is supported by a Rising Star Award from Cancer Prevention and Research Institute of Texas (CPRIT, R1108) and a grant from the National Institutes of Health (NIH, 1R01DK106418-01).

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Dan, J., Chen, T. (2016). Genetic Studies on Mammalian DNA Methyltransferases. In: Jeltsch, A., Jurkowska, R. (eds) DNA Methyltransferases - Role and Function. Advances in Experimental Medicine and Biology, vol 945. Springer, Cham. https://doi.org/10.1007/978-3-319-43624-1_6

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