The four dimensions of nucleosome chain folding

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DNA in eukaryotic cells is repeatedly coiled around histone proteins forming 'beads-on-a-string' chains of nucleosomes that are further folded into higher-order chromatin structures. Changes in the nucleosome chain packing density and DNA accessibility govern gene expression and repression during cell differentiation and tissue development. This project will investigate the 3-dimensional structures of nucleosome chains in the cell nucleus and their transitions over time in the course of tissue development and maturation, referred to as the 4th dimension. The outcomes of this research will provide crucial information for designing genetic and pharmacological tools capable of altering nucleosome chain folding and thus modulating epigenetic changes and developmental plasticity in differentiated cells and tissues. This project will be deeply integrated with graduate education and provide new research opportunities for undergraduate students, inspiring and training them for careers in STEM.The overall goal of this project is to reveal nucleosome chain folding motifs that characterize certain epigenetic states and are associated with locking down the underlying genes in mature cells and inhibiting tissue regeneration. The first research aim is to resolve the nanoscale chromatin structure of epigenetically distinct chromatin states in a reference human cell line. The second aim is to determine nucleosome chain transitions underlying chromatin condensation during mouse retina development. A unique technique, EMANIC (electron microscopy-assisted nucleosome interaction capture) will be applied to resolve nucleosome folding motifs. This technique will be used in conjunction with biochemical assays to link the nucleosome chain folding with specific epigenetic states and chromatin rearrangements. By integrating crucial structural information: nucleosome repeat length, internucleosomal interactions, and nucleosome chain flexibility with computational modeling, this project will provide new structural cues for engineering chromatin epigenetic states and modifying chromatin functions related to tissue developmental and regenerative processes.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.