“The Science of Connections: Bridging chromatin, synaptic plasticity, and neurophysiology”

Abstract

The Cremins Laboratory works at the spatial biology-technology interface to investigate the structure-function relationship of connections in the brain across the scales of chromatin, synapses, and circuits in normal neurophysiology and in neurological disorders. We have thus far focused in the nucleus on creating kilobase-resolution maps of higher-order folding of the chromatin fiber and understanding how classic epigenetic modifications work through long-range connections to govern genome function in neurodevelopment. We have developed and applied new molecular and computational technologies to elucidate chromatin folding patterns at kilobase-resolution genome-wide, thus discovering that long-range looping interactions in cis and inter-chromosomal interactions in trans change substantially during neural lineage commitment, somatic cell reprogramming, activation of post-mitotic neural circuits, and in neurological disorders. We have demonstrated that cohesin-mediated loops are necessary for the establishment of new gene expression programs in post-mitotic neurons, including the upregulation of genes encoding axon guidance, dendritic spine morphology, and synaptic plasticity during neuron maturation in vivo as well as activity-dependent transcription during neural stimulation in vitro. We have also identified cohesin-mediated loops anchored by divergently-oriented CTCF binding sites that are necessary and sufficient for the firing efficiency and localization of human replication origins during S phase re-entry after mitosis. Using fragile X syndrome as a natural perturbation, we have uncovered BREACHes (Beacons of Repeat Expansion Anchored by Contacting Heterochromatin) - rare inter-chromosomal interactions connecting heterochromatinized synaptic genes susceptible to repeat instability, thus providing early insight into the genome’s structure-function relationship. Here, I will present new unpublished data describing 3D genome miswiring in a human neuron model with rare familial Alzheimer’s mutations as well as the functional link among loops and activity-dependent gene expression during neural circuit activation in vitro and in vivo. The long-term goal of the Cremins lab is to elucidate how the genome’s structure-function relationship influences synaptic plasticity and neurophysiology during memory encoding and consolidation and how this goes awry in intractable neurological disorders.