Review
Epigenetic regulation of oligodendrocyte identity

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The interplay of transcription factors and epigenetic modifiers, including histone modifications, DNA methylation and microRNAs during development is essential for the acquisition of specific cell fates. Here, we review the epigenetic “programming” of stem cells into oligodendrocytes, by analyzing three sequential stages of lineage progression. The first transition from pluripotent stem cells to neural precursors is characterized by repression of pluripotency genes and restriction of the lineage potential to the neural fate. The second transition from multipotential precursors to oligodendrocyte progenitors is associated with the progressive loss of plasticity and the repression of neuronal and astrocytic genes. The last step of differentiation of oligodendrocyte progenitors into myelin-forming cells is defined by a model of derepression of myelin genes.

Section snippets

Epigenetic modulation of gene expression defines cell identity

One of the most exciting findings of the past few years has been the discovery that developmental processes are regulated by the crosstalk between transcription factors and epigenetic modulators of gene expression, including post-translational modifications of nucleosomal histones, changes in histone variants, chromatin remodeling enzymes, DNA methylation and microRNAs 1, 2, 3, 4, 5, 6. Collectively, these other factors have been defined as “epigenetic regulators” (epi=above), because they

Histone modifications

Chromatin modifiers comprise two large groups of enzymatic activities. One group is responsible for secondary modifications of the histones, whereas the other group includes enzymes using ATP to unwind nucleosomes and affect DNA/histone interactions. Post-translational modifications include the deposition or removal of acetyl, methyl, phosphoryl, sumoyl, ubiquitin and ADP-ribosyl groups from amino acids in the histone tails (Box 2). The most studied histone modifications are

Histone modifications

ESCs are characterized by the properties of self-renewal and pluripotency (i.e. the ability to generate all cell types of an organism), which depend on the interplay between the pluripotency-associated factors (i.e. Oct4, Sox2 and Nanog) and epigenetic modulators. To gain a mechanistic insight on the chromatin structure in ESC, genome-wide studies were conducted using chromatin immunoprecipitation (Box 1) and antibodies specific for pluripotency factors (i.e. Oct4, Sox2 or Nanog), for

Histone modifications

The concept of progressive restriction of cell lineage potential during differentiation applies not only to the transition from pluripotent ES cells to multipotent neural precursors but also to the restriction of multipotential neural precursors to lineage committed OPCs. This choice is characterized by the progressive decrease of genes such as Sox2 and chromatin modifications on astrocytic and neuronal genes that is initiated by the activity of histone deacetylases (Hdac) [53] and is

Histone modifications

Ultrastructural studies have described the characteristic appearance of compact chromatin in myelinating and non-myelinating oligodendrocytes [72]. Because compaction is associated with transcriptional repression, we propose a model of oligodendrocyte differentiation characterized by the progressive decrease of transcriptional inhibitors, followed by the upregulation of activators and then myelin gene expression (Figure 2). This model is supported by the detection of transcriptional inhibitors

Concluding remarks

The recent advances in regulation of gene expression have revealed the existence of an intricate regulatory network including transcription factors, chromatin modulators DNA methylation and microRNAs. This network defines the unique identity of each cell type, via a process of “epigenetic programming”. In this review, we discuss the subsequent transitions from pluripotent ESCs to myelinating oligodendrocytes. The overall concept is that repressive epigenetic regulations play a critical role for

Acknowledgments

Dr. Casaccia acknowledges funds from the National Institutes of Health–National Institute of Neurological Disorders and Stroke (NIH–NINDS) grants R01-52738, R01-42925 and R01NS042925-07S1. The authors apologize to all the colleagues whose outstanding work could not be cited owing to space limitations.

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