Since histone deacetylation and methylation are critical epigenetic modulators of gene expression during oligodendrocyte differentiation and myelin formation, they serve the purpose of establishing a “molecular memory,” which is stored in the nuclei of oligodendroglial cells. This memory is responsible for the downregulation and stable repression of inhibitory molecules in differentiated oligodendrocytes (Marin-Husstege et al. 2006
). In an attempt to understand the potential mechanisms underlying age-dependent decline of repair function, Shen et al. (2007)
reported the progressive loss of this “epigenetic memory” in oligodendrocytes during normal aging. Decreased histone deacetylation and repressive methylation of histone H3 tails were detected in older mice. The direct result of these epigenetic changes was the increased expression of inhibitory molecules, including Hes5, Ids, and Sox2 (Shen et al. 2007
). This partially explains why the responsiveness of oligodendrocytes to extracellular factors is decreased with aging and further suggests that chromatin modifications and changes in the “epigenetic memory” of oligodendrocytes may have profound effects on therapeutic outcomes.
Although not formally proven, these findings also suggest that similar epigenetic changes might affect the ability of progenitors in older brains to efficiently repair demyelinating lesions. Previous studies had suggested that remyelination failure was consequent to increased levels of inhibitory extracellular signals (John et al. 2002
) or insufficient levels of oligodendrogliogenic signals (Mastronardi et al. 2003
). However, it was shown that altering the levels of a single extracellular factor or signaling molecule was not sufficient per se to promote successful remyelination (Fancy et al. 2004
; Stidworthy et al. 2004
). Taken together, these results support a model of remyelination as a complex interplay between intrinsic changes and extracellular signaling cues.
An additional line of experimental evidence suggested the importance of aberrant modifications of nucleosomal histones in oligodendrocytes as part of the pathogenetic process leading to demyelinating disorders. Increased histone citrullination on arginine residues was reported to be increased in the normal-appearing white matter of MS patients and in animal models of demyelination (Mastronardi et al. 2006
). Citrullination of arginine residues on histone tails is catalyzed by peptidylarginine deiminase 4 (PAD4). Under normal conditions, PAD4 is cytosolically localized. However, under pathological conditions, such as in the presence of abnormally increased level of tumor necrosis factor α (TNFα), PAD4 is translocated to the nucleus, and its increased nuclear expression and activity catalyzes the citrullination of nucleosomal histones (Mastronardi et al. 2006
). Importantly, these molecular changes occur before the onset of symptoms in animal models of demyelination (Mastronardi et al. 2006
), indicating that TNFα-induced PAD4 nuclear localization and subsequent histone citrullination may be part of the etiopathogenesis of the disease.
The potential role of histone modifications in demyelinating disorders has also led to therapeutic attempts with histone-modifying drugs, but the results, at least in the EAE models, have led to controversial results. Administration of the HDAC inhibitor TSA to C57BL/6 mice with active immunization of MOG35–55
-induced EAE had favorable effects on spinal cord inflammation, demyelination volume, and axonal loss, possibly because of increased expression levels of anti-oxidants (i.e., glutathione peroxidase), glutamate transporters (i.e., excitatory amino acid transporter 2, EAAT2), and neuroprotective factors (i.e., insulin-like growth factor 2; Camelo et al. 2005
). However, also the administration of curcumin, a selective HAT (CBP/p300) inhibitor that decreases the total histone acetylation levels, had positive effects on EAE. When curcumin was administered to SJL/J mice with EAE induced by adoptive transfer of MBP-immunized immune cells, it inhibited the induction phase of the disease, possibly, by blocking IL-12 signaling pathway in T lymphocytes (Natarajan and Bright 2002
Together, these results reveal the need for the development of more specific therapies aimed at targeting epigenetic modulators only in specific cell populations.