Oligodendrocytes are specialized glial cells of the central nervous system, whose membrane forms the insulating coating (i.e. myelin) that wraps the axons and allows fast axonal conduction. These cells derive from progenitors that differentiate into myelin-forming oligodendrocytes and are known to play an essential role in modulating neuronal function. Thus, improper progenitor differentiation or myelin formation is detected in distinct neurological disorders and has important clinical consequences. Recent studies have shown that the early progenitor stage is marked by global acetylation of lysine residues on nucleosomal histones and is followed by global histone deacetylation;the latter being required for the initial decrease in gene repression that is essential for the proper onset of myelination1,2. Moreover, studies using pharmacological inhibitors of HDACs3,4, gene silencing in primary cultures of progenitors5 and analysis of zebrafish mutants6 and knockout mice7,8 have clearly shown functional relevance of histone acetylation and deacetylation for oligodendrocyte biology. However, the specific role of this and other mechanisms of epigenetic regulation in the functioning of the brain are still poorly understood. Therefore, novel research tools useful to decipher the mechanistic insights of epigenetic gene expression in the development of brain diseases are of great interest. This proposal attempts to address this need by developing chemical probes with application to study the effect of histone deacetylation states on the development of neurodegenerative disorders associated with demyelinating disorders. Thus, based on the cumulative evidences above presented, we hypothesized that chemical inhibitors of acetyltransferase activity, which favor deacetylated states of lysine residues on nucleosomal histones, could be efficient promoters of the progression of oligodendrocyte progenitors towards a more differentiated state. More specifically, we reasoned that inhibiting the function of the bromodomain of CBP could be a novel and efficient way of favoring nucleosomal histones deacetylation. To this end, this research project focus on the design, synthesis and biological evaluation of inhibitors of the bromodomain of the transcriptional coactivator CBP.
Improper progenitor differentiation or myelin formation is detected in distinct neurological disorders and has important clinical consequences. The present proposal attempts to develop inhibitors of the bromodomain of the transcriptional coactivator CBP as chemical probes to study neurodegenerative diseases associated with demyelinating disorders.
|Gacias, Mar; Gerona-Navarro, Guillermo; Plotnikov, Alexander N et al. (2014) Selective chemical modulation of gene transcription favors oligodendrocyte lineage progression. Chem Biol 21:841-54|