Role of the chromatin remodeling Tip60/ Ep400 complex in myelin-forming glia

点击翻译按钮获取中文摘要

Processes of cellular development and differentiation are frequently linked to substantial changes in chromatin that are brought about by histone-modifying enzymes and chromatin-remodeling complexes. The multisubunit Tip60/Ep400 complex is involved in histone acetylation via its Tip60 subunit, as well as in chromatin remodeling by catalyzing the exchange of histone H2A against histone H2A.Z via its Ep400 subunit. Successful formation of the Tip60/Ep400 complex requires the presence of both subunits. In the last funding period, we have used glia-specific deletion of the Ep400 subunit to show that the Tip60/Ep400 complex is important for proper development of myelinating glia in mice. In particular we have documented essential roles of the complex for terminal differentiation and myelin formation in Schwann cells of the peripheral nervous system as well as in oligodendrocytes of the central nervous system. Whereas Schwann cells primarily require the Tip60/Ep400 complex for proper termination of the precursor cell program, oligodendrocytes rely on the complex for induction of the differentiation program and for protection of their genome during the vulnerable phase of differentiation. Apart from the Myrf gene, functionally relevant direct target genes have not yet been identified for the Tip60/Ep400 complex in oligodendroglial cells. Deletion of the Tip60 subunit in oligodendrocytes leads to similar disturbances in the differentiation process as previously observed after Ep400 deletion. However, Tip60 deletion causes additional defects in oligodendroglial development at the progenitor cell stage that are attributable to a second function of Tip60 as a transcriptional co-activator outside the chromatin remodeling complex. It is the aim of the current proposal (i) to obtain a complete picture of the molecular mode of action of Tip60 and Ep400 in the context of oligodendroglial development by comparing oligodendroglial properties and expression profiles in Tip60 and Ep400 mouse models in combination with genome-wide mapping approaches for binding sites of Tip60 and Ep400 as well as induced chromatin changes, (ii) to identify functionally relevant direct target genes and (iii) to separate common functions of Tip60 and Ep400 as part of the chromatin remodeling complex from Tip60-specific co-activator functions for oligodendroglial transcription factors such as Sox10. Our work will not only yield new insights into oligodendroglial development und disease-relevant disturbances, but will also be instrumental in advancing our knowledge on the function of chromatin remodelers from the commonly studied tissue culture settings to complex systems in vivo.