DNA methylation and methylcytosine oxidation in cell fate decisions

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Changes in cellular phenotypes and identities are fundamentally regulated by epigenetic mechanisms including DNA methylation, post-translational histone modifications and chromatin remodeling. Recent genome-wide profiles of the mammalian DNA ‘methylome’ suggest that hotspots of dynamic DNA methylation changes during cell fate transitions occur at distal regulatory regions with low or intermediate CpG densities. These changes are most prevalent early during the course of cellular differentiation and can be locally influenced by binding of cell-type specific transcription factors. With the advent of next-generation quantitative base-resolution maps of 5-methylcytosine and its oxidized derivatives and better coverage of the genome, we expect to learn more about the true significance of these DNA modifications in the regulation of cell fate choices.

Highlights

► DNA methylation changes at distal elements of low CpG densities regulate cell fate. ► These changes are most prevalent during the early stages of lineage commitment. ► Cell-type specific transcription factors locally influence DNA methylation.

Introduction

In mammalian genomes, the major epigenetic modification of DNA is methylation at the 5-position of the cytosine base, often at symmetrical CG dinucleotides (CpG). DNA methylation is implicated in numerous cellular processes during development including genomic imprinting, X-chromosome inactivation and transposon silencing [1]. DNA methylation at promoters is often associated with inhibition of transcriptional activity, but more recent genome-wide profiling of the DNA ‘methylome’ in plants and animals is revealing new biological functions of this mark in gene regulation [2, 3]. In this review, we discuss recent genome-wide location profiles of 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) in different mammalian cell types, focusing on models of cellular differentiation from pluripotent or multipotent states toward restricted somatic cell lineages. This subject has been recently reviewed [4, 5, 6] but continues to evolve with increasing depth and coverage of whole genome sequencing efforts. Owing to space limitations, we will not discuss the role of DNA methylation in the specification of germ cells and in cancer, for which we refer the reader to other recent reviews [7, 8, 9].

Section snippets

Dnmts and Tet proteins in stem cells and development

In somatic cells, DNA methylation is generally stable because the maintenance DNA methyltransferase Dnmt1 faithfully restores methyl marks on newly replicated DNA strands. By contrast, dynamic genome-wide changes in DNA methylation occur during early embryogenesis, most notably in the paternal pronucleus of the zygote where replication-independent demethylation occurs shortly after fertilization, and during reprogramming of primordial germ cells [10]. Subsequently, methylation profiles in the

DNA methylation profiling in different cell states

Although promoter methylation contributes to repression of core pluripotency genes, such as Oct4 and Nanog, it is only a second-tier epigenetic change, occurring after histone H3(K9) methylation and heterochromatinization, to stably inhibit reactivation of these genes during differentiation [32] (Figure 2). Low CpG content promoters (LCP), which are generally associated with tissue-specific genes, tend to be constitutively highly methylated; on the other hand, high CpG content promoters (HCP),

Tracking DNA methylation dynamics during cellular differentiation

Early studies suggested that DNA methylation can function in a highly locus-specific manner, involving in some instances changes at a single cytosine, to regulate lineage-specific development (reviewed in [4, 5]). However, these studies have been obscured by genome-scale data that, as described above, illustrate more often than not that promoter methylation and transcriptional activity do not follow each other in an obligatory fashion.

The tracking of DNA methylation changes at genome-wide scale

Mapping 5-hydroxymethylcytosine — a new methylation variant in disguise

A major limitation of bisulfite-based approaches to methylation profiling is the inability to discriminate between 5mC and 5hmC [23]. Thus, all current state-of-the-art high resolution DNA methylome maps still require reinterpretation since what has been previously called methylation is really a sum of 5mC and 5hmC. For instance, the high gene body methylation levels of expressed genes may indicate enrichment of 5hmC at the expense of 5mC, as evident in terminally differentiated neural cell

Conclusions and perspectives

The recent advances in DNA methylome studies have rapidly changed previous perceptions of DNA methylation. We summarize with the following points (Figure 4):

  • (1)

    DNA methylation/hydroxymethylation changes at distal elements with low to intermediate CpG densities are probably more informative than changes at promoters/gene bodies in regulating cell fate.

  • (2)

    DNA methylation changes are most prevalent during the early stages of lineage commitment.

  • (3)

    Cell-type specific transcription factors can influence DNA

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We apologize to those whose work could not be cited due to space limitations. Research in the laboratory of Kian Koh is supported by the Fonds voor Wetenschappelijk Onderzoek Research Foundation — Flanders (G.0C56.13N and G.0632.13), the Ministerie van de Vlaamse Gemeenschap and the Marie Curie Career Integration Grant (PCIG-GA-2012-321658). Research in the lab of Anjana Rao is supported by NIH R01 grants HD065812, AI44432 and CA151535, grant RM1-01729 from the California Institute for

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