A striking feature of the nervous system is its continual adaptation to environmental cues throughout the entire lifespan of an animal. Environmental stimuli trigger changes in neuronal activity states that drive adaptive modifications to neuronal morphology and connectivity. Despite essential functions in promoting plasticity, neuronal activity presents a risk to the genome and epigenome, as activity-induced transcription proceeds via induction of DNA breaks at gene regulatory elements. The chromatin around activity-inducible genes is rapidly remodeled as the DNA itself is cut, unwound, and eventually re-sealed in a process that has the potential to create permanent mutations. How do neurons balance the need for plasticity with the relentless assault on their epigenomes that occurs in response to stimuli? What mechanisms safeguard neuronal genomes and epigenomes, and how are these mechanisms adapted in organisms of vastly different lifespans? Can we identify the molecular basis of interventions that reverse genome damage to restore youthful neuronal function? Our lab tackles these questions using a multidisciplinary approach that integrates biochemistry, single-cell genomic assays, cell biology, and neuronal circuit function.
Neuronal Chromatin Modifiers in Transcriptional Fidelity
We discovered an activity-dependent protein complex, NPAS4:NuA4, that both induces activity-dependent transcription and stimulates the repair of transcription-coupled DSBs. We aim to characterize how this complex and other repair factors work downstream of neuronal activity to preserve transcriptional fidelity and suppress mutational accumulation across a range of cell types in vivo. We use mouse models to study how inactivation of the NPAS4:NuA4 complex components influences developmental and aging phenotypes.
Activity-Dependent DNA Repair Mechanisms in Humans
Unlike mice that live less than 3 years, human neurons must survive 80-100 years of repeated stimulation. The extended lifespan of humans compared to rodents suggests that neuronal genome preservation is especially essential for sustaining neuronal vitality and preventing disease. We are dissecting mechanisms of human-specific activity-dependent transcription and DNA repair using human brain tissue and IPSC-derived neuronal cultures.
Sleep in Neuronal Rejuvenation and Nervous System Longevity
Neuronal function can be rejuvenated by a variety of interventions, such as diet and cognitive training, yet how the fundamental process of sleep preserves neuronal longevity remains largely unknown. Both acute and sustained loss of sleep increases the risk of developing degenerative diseases and can shorten lifespan across a variety of species. Why is sleep so critical and how does it restore function at the genome level in individual cell types of the nervous system? We are investigating the molecular factors that regulate sleep-dependent genome and epigenome integrity across neuronal ensembles in the brain and body, using both genomic techniques and behavioral assays.