Memory emerges through connections across the brain. At the smallest scales, DNA folds into complex three-dimensional structures within the nucleus. At larger scales, neurons communicate through synapses and neural circuits that shape learning, behavior, and experience.
Our research investigates how these systems work together.
Understanding the Science of connection.
Specifically, we study the structure-function relationships that connect chromatin, synapses, and neural circuits in both healthy brains and neurological disorders. By understanding how genome organization influences neural function across scales, we aim to uncover the mechanisms that govern memory formation, persistence, and dysfunction.
Using approaches spanning neurobiology, epigenetics, genome engineering, sequencing, imaging, human organoids, and electrophysiology, we investigate how chromatin in the nucleus and RNA at the synapse communicate during memory encoding, consolidation, and recall.
Foundational Discoveries
When our lab was founded, it remained unclear how genomes are folded in a cell type-specific manner below the resolution of a megabase, and whether higher-order genome folding could directly influence genome function.
Over the past decade, our research has helped reveal how the three-dimensional organization of the genome influences what genes are turned on, how cells transition between states, and how these processes change in both healthy and diseased brains. These discoveries have provided foundational insights into the genome's structure-function relationship in the mammalian brain.
Our major contributions include:
Developed and applied new molecular and computational technologies to map chromatin folding at kilobase resolution across the genome, revealing substantial changes in chromatin loops and inter-chromosomal interactions during neural lineage commitment, somatic cell reprogramming, neuronal stimulation, and neurological disorders.
Demonstrated that cohesin-mediated loops are necessary for establishing new gene expression programs in post-mitotic neurons, including genes involved in axon guidance, dendritic spine morphology, synaptic plasticity, neuronal maturation in vivo, and activity-dependent transcription during neural stimulation in vitro.
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.
Discovered BREACHes (Beacons of Repeat Expansion Anchored by Contacting Heterochromatin), rare inter-chromosomal interactions connecting heterochromatinized synaptic genes susceptible to repeat instability in fragile X syndrome.
Uncovered severe 3D genome miswiring linked to synaptic gene expression dysregulation and excitatory-inhibitory neuron state shifts associated with familial Alzheimer's disease mutations.
Demonstrated substantial rewiring and persistence of long-range looping interactions during fear memory encoding and consolidation in vivo and neural analogs of learning in vitro.
Chromatin Architecture & Genome Function
Our work begins with chromatin, the three-dimensional folding of the genome within the nucleus.
We investigate how chromatin architecture influences gene expression during neural development, maturation, activity-dependent plasticity, and disease. By adding a spatial dimension to our understanding of genome regulation, we seek to uncover how structure influences function throughout the brain.
Chromatin-Synapse Communication
One of the lab’s primary research interests is understanding how communication occurs between the nucleus and the synapse.
We study how genomic organization influences synaptic function and how neuronal activity reshapes chromatin architecture. These interactions may play a fundamental role in memory encoding, consolidation, and recall.
Memory Persistence & Neural Plasticity
Memories can last for decades despite continual turnover of proteins and RNA throughout the brain.
We study the mechanisms that allow information to persist across time and biological change, exploring how chromatin dynamics, synaptic plasticity, and neural circuits work together to support long-term memory.
Memory Dysfunction & Neurological Disease
Understanding how memory functions in healthy brains provides a foundation for understanding what happens when these systems break down.
Our research seeks to illuminate the biological mechanisms underlying memory dysfunction in neurodevelopmental, neurodegenerative, and neuropsychiatric disorders, including repeat expansion disorders, aging-related disease, and PTSD.
Future Research
Building on our foundational discoveries, we are pursuing new research directions that explore how information flows between chromatin, synapses, and neural circuits.
Synapse → Nucleus
Nucleus → Synapse
Synapse-Resolution Molecular Neural Connectome Maps
Chromatin Control Over Genome Instability
Genome Structure-Function
Disease Mechanisms
Support Our Research
Our research is made possible by a combination of grants and philanthropic gifts. If you are excited about the work we are doing and are interested in contributing, please get in touch.
Lab Updates
News, milestones, publications, events, and discoveries from across the Cremins Lab community.
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