ReviewDefining the chromatin landscape in demyelinating disorders
Introduction
One of the first concepts concerning the “chromatin landscape” of a cell was that of a “packaging” system to fit the entire genomic content into a single nucleus (Kornberg and Thomas, 1974). However, this concept has evolved over the years and we are now recognizing the menagerie of chromatin modifications that function as dynamic modulators of gene expression (see Li et al., 2007). Moreover, the topological features of chromatin are not constant but rather are composed of areas of condensation and de-condensation, defining “peaks and valleys” in the chromosomes and affecting the appearance of a specific “chromatin landscape” that changes with the developmental and differentiative state of the cell. The complexity and intricacy of this system becomes vaster by the day as we discover novel modifications and the enzymes facilitating these changes, but the ultimate challenge will be to define how these modifications might contribute to development and disease.
Over the past few years, our understanding of the role of epigenetics during oligodendrocyte development and myelin formation has rapidly progressed. During differentiation, a global increase in histone deacetylation and chromatin compaction is necessary for oligodendrocyte lineage progression (Marin-Husstege et al., 2002, Shen et al., 2005). Specifically, repression of transcriptional inhibitors such as Hes5 (Kondo and Raff, 2000a, Liu et al., 2006), Sox11 and Tcf4 (Fancy et al., 2009, He et al., 2007b, Ye et al., 2009), and Id2 and Id4 (Kondo and Raff, 2000b, Marin-Husstege et al., 2006, Samanta and Kessler, 2004) is a necessary feature of this process (He et al., 2007a). The expression of these inhibitors is modulated by a series of post-translational changes on lysine residues in the tail of nucleosomal histones that allow chromatin de-condensation at the progenitor stage and condensation during maturation.
In this review, we present an overview of the chromatin landscape in oligodendrocyte lineage cells. We discuss how it potentially may take shape during development and how perturbations to this landscape can affect remyelination capacity. We shall briefly mention changes relative to the acetylation and methylation profiles of histone tails, as these have been discussed extensively in other reviews (see Copray et al., 2009, Shen and Casaccia-Bonnefil, 2008), and turn our focus towards other modifications have yet to be studied extensively in demyelinating disorders.
Section snippets
Normal oligodendrocyte development and maturation
Oligodendrocyte differentiation and myelin formation is a complex developmental process, requiring the coordinated action of transcription factors (Nicolay et al., 2007, Wegner, 2008), the chromatin machinery (Li et al., 2009, Liu et al., 2007a, Sher et al., 2008), and additional factors affecting RNA stability and content. To understand how aberrant changes to the chromatin landscape can affect the repair process after demyelination, we must first examine the normal profile of this
The chromatin landscape shifts in demyelinating disorders
The chromatin landscape that takes shape during normal oligodendrocyte development and myelin formation is a complex network requiring the coordinated action of multiple epigenetic pathways. And with this idea in mind, we can begin to see how perturbations to any one of these processes can affect oligodendroglial maturation and myelination. Specifically, we examine this landscape in terms of the changes that affect remyelination capacity, as this process utilizes a similar developmental program
Disease models provide a glimpse of changes that are poorly understood in demyelinating disorders
Great strides have been made with classifying the epigenetic mechanisms that contribute to changes seen in demyelinating disorders. However, most of these findings are limited to features that have been studied extensively in oligodendrocytes, such as histone modifications. For other aspects of the chromatin landscape, such as DNA methylation and miRNAs, we can turn to other systems to help us understand their role in disease.
Summary
Our view of the chromatin landscape that takes shape during oligodendrocyte development, myelination, and remyelination is only at the cusp of what is still to be found. The interplay of so many epigenetic factors makes it a difficult process to characterize this landscape but we have slowly begun to unravel it. And with each discover, unknown factors of normal developmental are revealed and the possibilities for therapies are expanded with each new target.
Acknowledgments
P.C. acknowledges the support of NIH-NINDS, grants RO1-NS42925 and RO1-NS52738. J.L.H. was supported by a fellowship NIH T32GM007280 and by the Foundation of the Consortium of Multiple Sclerosis Centers.
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