Histone deacetylation in oligodendrocyte differentiation

Icahn School Of Medicine At Mount Sinai, New York NY

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Abstract

DESCRIPTION (provided by applicant): The proposed experimental plan is an extension of our previous study aimed at defining the histone modifications responsible for the differentiation of progenitors into oligodendrocytes, the myelin-forming cells of the central nervous system. In the parent grant, R01-NS42925 we requested funds to study the regulation of histone deacetylation during developmental myelination. Our lab has been very productive in this respect and we have continued to make progress in demonstrating the importance of histone deacetylation during repair and aging. Thus, understanding the mechanisms leading to successful differentiation of progenitors into myelinating cells has important implications not only for dysmyelinating conditions and developmental disorders, but also for adult pathologies associated with oligodendrocytic loss (i.e. multiple sclerosis, traumatic brain injury, spinal cord injury). One interesting aspect of post-translation modifications of nucleosomal histones linked to deacetylation, is their association with additional repressive modiciations occurring on specific lysine residues, such as tri-methylation of K9 and inactivating demethylation of K4 on histone H3. Preliminary data from our lab have revealed distinctive patterns of histone methylation and demethylation in myelinating and non myelinating cells and identified the associated enzymatic activities. Because histone deacetylases HDAC1/2 bind to the enzymes responsible for altering the methylation status of histone H3, we proposed to extend our analysis to the interaction between deacetylation and distinctive changes of histone methylation during progenitor differentiation into myelinating or non-myelinating cells. This will be accomplished by hiring new personnel and purchasing products and services to enhance the progress of the proposed experimental aims. The new experiments will address the functional role of histone K9 methylation in the acquisition of a myelinating identity and K4 demethylation in the acquisition of a non-myelinating identity, thereby unraveling new mechanisms of regulation of differentiation and lineage commitment, with important implications for repair and cell objectives of the American Recovery Act, since it will require the employment of two post-doctoral fellows and one research assistant, the expansion of our animal colony, the purchase of supplies and the contract of services from American Companies specialized in biotechnologies. Due to the well defined experimental plan for each aim and the availability of all the techniques and reagents in the laboratory we are highly confident that the proposed project will be completed within the two-year time frame. PUBLIC HEALTH RELEVANCE: The proposed experiments address the molecular mechanisms responsible for the differentiation of progenitors into myelinating or non-myelinating oligodendrocytes and therefore will bear important consequences for the future design of strategies aimed at remyelination in a wide range of neurological disorders characterized by myelin loss, including multiple sclerosis, traumatic brain injury, metabolic and vascular disorders with white matter damage. By addressing the molecular mechanisms responsible for reversible and stable programs of gene expression underlying the commitment of cells to a specific lineage, this study bears relevance to a better understanding of glial tumor biology. Finally, by addressing mechanisms regulating the chromatin components responsible for cellular identity, these study are highly relevant to cellular reprogramming, a concept of high relevance to regenerative medicine.