3DCellID · How 3D genome organization allows cells to learn and remember their identity

Through development cells establish distinct identities, i.e. stable cellular states, with over 2,000 such cellular states in human. Cells can maintain their identity for decades and through cell divisions, a phenomenon known as ""epigenetic memory”. Loss of this stability is a hallmark of aging and diseases, including cancer. While much has been learned about the individual molecular processes contributing to cellular memory, it remains unclear how these dynamic processes work together on a cell scale, yielding a long-term memory of cell identity. 3D genome organization is now emerging as a leading factor in the establishment and maintenance of epigenetic memory, with a potential to integrate many individual processes. Yet how memory is established through cellular experiences, and how it deteriorates in aging and disease remain largely unknown. 3DCellID will use approaches from polymer physics and active matter theory to unravel the principles of the establishment of 3D epigenetic memory, and its deterioration. First, we will investigate the role of genome “anchoring” to the nuclear lamina. Loss of such anchoring is associated with accelerated ageing, progeria syndrome. Working in a world-leading 3D genomics group, I will develop generic physical models to illuminate how interactions with the lamina shape genome organization to yield robust epigenetic memory. I will then validate those models against existing and emerging experimental data for progeria as well as for normally aging cells. Second, we will focus on the establishment of epigenetic memory through cellular learning. To address this I will investigate how the interplay of 3D genome organization and multiple chromatin marks can give a cell an associative memory of past cell states and experiences. Taken together, 3DCellID will yield mechanistic insight into how 3D genome folding interacts with dynamic epigenetic patterns to establish, maintain and eventually dismantle cellular identity.""