Epigenetic regulation of centromeric chromatin and its role in chromosome segregation

• Applicant: Professorin Sylvia Erhardt, Ph.D.
• Subject Area: Cell Biology
• Term: from 2011 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 195149126

Centromeres are an essential chromatin domain for accurate chromosome segregation during mitotic and meiotic cell division. Centromeric chromatin differs from non-centromeric chromatin epigenetically; i.e. by the high abundance of the histone variant CENP-A that replaces the canonical histone H3 in some nucleosomes at centromeric chromatin. CENP-A loading is regulated by a finely balanced system, and this system depends upon specialized loading factors that deposit CENP-A to centromeric regions. While misincorporation of CENP-A is a hallmark of both cancer and birth defects, current evidence suggests that cells have also evolved certain mechanisms that promote non-centromeric CENP-A incorporation. A main goal of this continuation grant is to understand the function, regulation, and differences of centromeric and non-centromeric CENP-A loading and localization. In the initial funding phase we discovered that factors involved in chromatin remodeling are required for correct CENP-A incorporation, especially under genotoxic stress. We will continue our research by analyzing the precise composition and regulation of these chromatin-remodeling complexes. We will characterize their mode of action on centromeric and non-centromeric CENP-A loading in normal physiological cells and under genotoxic stress. The precise molecular characterization of these complexes and an understanding of their influence on chromatin will then provide crucial insights into the role CENP-A plays in DNA damage response.We also identified a new loading pathway for non-centromeric CENP-A in the initial funding period. We will continue our research by determining the precise players and mechanisms of non-centromeric CENP-A loading, and how chromatin steady state influences centromeric and non-centromeric CENP-A. We will combine our understanding of CENP-A loading mechanisms with the role of newly identified CENP-A post-translational modifications to obtain a comprehensive picture of the epigenetic regulation of centromere identify and its differential regulation to non-centromeric regions. Our findings may help to understand how cells react to, and compensate for, genotoxic stress via chromatin remodeling. Ultimately, a better understanding of how cells avert genome instability may allow us to identify misregulations that lead to tumorigenesis.

• DFG Programme: Research Grants