Oligodendrocytes are the myelinating cells of the central nervous system, making their function critical for axonal survival and proper conduction of action potentials. Oligodendrocytes are derived from oligodendrocyte progenitors (OPCs) and their differentiation is orchestrated by a balance of epigenetic repression by histone and DNA modifying enzymes and transcriptional activation by chromatin remodelers. These epigenetic events have been shown to be modulated by both chemical and mechanical external stimuli. While the repressive events driving oligodendrocyte differentiation have been well-studied, significantly less is known about the transcriptional activation by chromatin remodelers and how their activity is modulated by extrinsic signals. Prior studies have shown that compressive force induces both enhanced myelination and a rapid influx of monomeric actin into the OPC nucleus. Monomeric actin has been shown to bind strongly to an actin-related protein called ACTL6a, which is a component of the SWI/SNF chromatin remodeling complex, whose function is critical for oligodendrocyte differentiation. My proposal thus utilizes both in vitro and in vivo models to investigate the mechanism through which ACTL6a modulates the epigenetic events that regulate oligodendrocyte differentiation. Using characterizations of mice with Actl6a ablated at various stages of the oligodendrocyte lineage, I found that ACTL6a is critical for early OPC differentiation. My preliminary data additionally revealed an increase in ACTL6a in response to both chemical and mechanical inducers of differentiation. Biochemical investigation further revealed that ACTL6a interacts with several components of the transcriptional machinery and the SWI/SNF chromatin remodeling complex. Based on these results, my proposal tests the hypothesis that ACTL6a modulates OPC differentiation through the recruitment of chromatin remodelers and the transcriptional machinery to activate gene expression. The results of this proposal will ultimately shed light on a critical mechanism through which ACTL6a, an actin-related protein, modulates chromatin remodeling and the epigenetic landscape of OPCs during differentiation and developmental myelination.
Myelination is essential for proper brain function and results from the differentiation of oligodendrocyte progenitors into myelinating oligodendrocytes. Based on solid preliminary data, this proposal defines the role of ACTL6a (an actin-related protein, binding to ATP-dependent chromatin remodelers and transcriptional machinery components) for myelin formation.
