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Elucidating the propagation and function of H2A and H2B modifications across DNA replication

Periodic Reporting for period 1 - H2AH2B_Propagation (Elucidating the propagation and function of H2A and H2B modifications across DNA replication)

Reporting period: 2020-09-01 to 2022-08-31

Genetic information is packaged into the cell nucleus by histones proteins, which, together with their modifications, regulate gene expression and thus control which cell type is formed and maintained over time (epigenetic memory). However, whenever the cell divides, it duplicates its genetic information during DNA replication, which also requires double the amount of histone proteins and their modifications to faithfully propagate epigenetic memory. If the appropriate copying of these modificiations fails, the memory of what genes have to be expressed can get lost, which is a recurrent problem in aging and diseases such as cancer. Only few studies so far have investigated how the propagation of epigenetic memory mechanistically works during DNA replication, and they have only looked at histone proteins H3 and H4, while histone proteins H2A and H2B have not been studied in their role in that process. In this project, I sought to uncover the exact mechanisms and properties of how H2A and H2B proteins and their modifications are handled during DNA replication. I could demonstrate that epigenetic information on H2A and H2B is also propagated during DNA replication in a way that is independent of H3-H4 and that it is important to accurately restore epigenetic information on histones H3 and H4. This newly identified mechanism explains how cells remember their cell type also during DNA replication and will help us in the future to understand the issues arising in aging and cancer, where epigenetic cell memory is lost.
I have adapted novel technologies from the host lab to study histones H2A and H2B and their modifications during DNA replication. I could show that all examined modifications on H2A-H2B are accurately propagated during DNA replication in a way that is independent from H3-H4 and thus constitutes a novel, additional layer of propagating epigenetic memory. After DNA replication, the modifications on H2A and H2B are restored very quickly, explaining how the cells can continue to regulate gene expression right after DNA replication. Furthermore, these dynamic modifications on H2A and H2B (short-term memory) are important to restore slow, stable modifications on H3-H4 (long-term memory) and thus are directly required to maintain the regulatory landscape. These novel insights are being published soon and will be of major interest for many researchers working in the fields of epigenetics, DNA replication and histone modifications. The publication of this work as an open-access article will ensure widespread dissemination of these findings to the broad community
The identification of a novel, independent pathway propagating and stabilising epigenetic memory will be of major importance to understand the molecular details of how a cell remembers its identity and function. This has a direct societal impact as loss of epigenetic cell memory is often prevalent in aging and diseases like cancer. Hence, understanding the details of how cells remember their identity in healthy cells (that we studied in this project) will be instrumental to understand what goes wrong in senescent (aged) cells or cancer cells. These important results will be published very soon in an renowned journal with broad audience as an open-access article, thus ensuring optimal dissemination.
Summary of the scientific findings in this project

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