Chromatin and Cell Fate

Summary

Epigenetic information is written in chromatin. But how exactly do epigenetic mechanisms operate on the molecular level? How do chromatin alterations contribute to cell fate transitions? How does the environment influence these processes? And how does the metabolic state of a cell impact on its chromatin structure and its epigenetic memory?

These are questions we address in the lab. Studying stem cells and cancer we focus on molecular aspects of epigenetic regulation and on the question whether we can translate this knowledge into diagnostic and therapeutic tools for the management of disease.

Our Research

In our scientific approach we combine biochemical techniques, cell culture and ultrasequencing of enriched chromatin fractions to address mechanistic and functional aspects of epigenetics. As model system for cell differentitiation we are currently using mouse embryonic stem cells, human primary keratinatinocytes and myoblasts. Key findings are validated in vivo. For the study of cancer we combine established cell lines, de novo transformation of primary cultures and patient tissue.

Ongoing projects in the lab fall into four main themes:

• The study of chromatin regulators affecting embryonic stem cell fate.
• The link between metabolic and epigenetic alterations in skin cancer.
• The regulation and molecular function of histone variants.
• The role of macroH2A in differentiation and tissue regeneration.

The longest ongoing line of our research focuses on the regulation and function of the histone variant macroH2A. Histones form the proteic core of the nucleosome, which is the modular building block of chromatin structure. MacroH2A is the only histone with a tripartite structure consisting of a N-terminal histone-fold, an intrinsically unstructured linker domain and a C-terminal macro domain. The incorporation of a macroH2A protein into the nucleosome places the macro domain in close proximity to the symmetrical axis and can be considered as the most extensive chromatin modification at the building block level.
From a large set of loss-of-function studies we could conclude that macroH2A is required for the establishment and maintenance of differentiated epigenomes. Although macroH2A is a well-established repressor, we now know that its pro-differetiation function in embryonic stem cells depends at least in part on a poorly understood function in transcriptional activation (Creppe, 2012a). Want to know more? Please have a look at our recent reviews on macroH2A (Creppe, 2012b; Posavec, 2013). Our current work we study the context-dependent function of the macro domain and the regulation of the locus-specific incorporation of macroH2A.
 

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