The Cremins Laboratory works at the spatial biology-technology interface to investigate the structure-function relationship of connections across the scales of chromatin, synapses, and circuits in the developing and diseased mammalian brain. Neurons exhibit elaborate structures at multiple scales, including diverse long-range axonal projections to form circuits, a range of complex dendritic spine geometries at the synapse, and the folding of the 10 nm chromatin fiber into compartments, topologically associating domains (TADs), and long-range looping interactions in the nucleus. 

We have thus far focused on the nucleus to elucidate chromatin’s higher-order folding patterns at kilobase-resolution during neural lineage commitment, maturation, activity stimulation, and in neurological disorders. In mammals, the genetic sequence is >2 meters when stretched out end-to-end. It is folded into exquisite structures to fit into a nucleus roughly the size of a pin’s head. At the lab’s inception, it remained unclear how genomes are folded in a cell type-specific manner below the resolution of a Megabase, and whether and how higher-order folding could deterministically influence genome function. Our major contribution has been to provide early foundational insights into the genome’s structure-function relationship. We have elucidated how chromatin works through long-range mechanisms to govern the establishment of new gene expression, repeat instability, and replication origin firing patterns when mammalian cells transition states in the healthy and diseased brain.

Overall, by adding a spatial, third dimension to our understanding of chromatin’s regulatory mechanisms, the Cremins lab has uncovered foundational basic insights into the genome’s structure-function relationship in the mammalian brain and in neurological disorders. Looking forward, the lab will focus on mechanisms underlying chromatin-synapse communication and a fundamental mystery in neuroscience: how memory is stored over decades despite rapid turnover of proteins/RNAs. The long-term goal of the Cremins lab is to bridge chromatin folding, synaptic plasticity, and neurophysiology to elucidate how the genome’s structure-function relationship influences synaptic defects in intractable neurodevelopmental, neuropsychiatric, and neurodegenerative disorders.