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Mechanisms of Chromatin-based Epigenetic Inheritance

Final Report Summary - EPIMECHANISM (Mechanisms of Chromatin-based Epigenetic Inheritance)

DNA constitutes the molecular template of genes. Genes are stably inherited across generations because the DNA molecule is stable and accurately duplicated and partitioned during cell division, thereby being faithfully transmitted to the next generation. Some protein structures that are bound to the DNA are also stable inherited. In this project we asked how this works and aimed to understand which proteins are stably bound to DNA long enough to be transmitted during cell division, how are such structures duplicated and how is accurate duplication achieved? We focused on the human centromere, a protein complex on chromosomes that is important for partitioning chromosomes during cell division. We discovered that one protein, CENP-A, that is a family member of DNA-bound histone proteins, is very stable and survives through multiple cell divisions. We identified new proteins that ensure that CENP-A remains bound to chromatin at all times. We developed novel ways of measuring how histone proteins are inherited, not only at the centromere but genome wide. Further, we determined the size and precise architecture of the centromere protein complex and we discovered that the duplication of the centromeric protein complex occurs only once per cell cycle. We found the key control molecules that ensure this “once and only once” per cell cycle mechanism. This is important to ensure the correct size and ultimately the correct functioning of the centromere to drive cell division. Finally, we succeeded in developing methods to create and isolate new centromeres from scratch. These rare events provide us with novel insights of how centromeres are formed and evolve.