Molecular Mechanisms of Nervous System Longevity and Rejuvenation
The Pollina Lab is broadly interested in identifying the molecular mechanisms that preserve longevity across the diverse cell types of the nervous system. Throughout our lives, neurons retain a remarkable level of plasticity that facilitates learning, memory, and behavior. As animals encounter new sensory stimuli and learn complex behaviors, these experiences trigger changes in neuronal activity patterns that drive dynamic alterations to the transcriptome, epigenome, and the genome itself. Despite essential functions in promoting plasticity, neuronal activity presents a risk to the genome, as activity-driven transcription induces DNA breaks at gene regulatory elements. During transcription, DNA itself is cut, unwound, and re-sealed in a process that has the potential to create permanent mutations. What mechanisms safeguard neuronal genomes, 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?
In the Pollina lab, we aim to identify mechanisms of transcriptional control and epigenome integrity that preserve neuronal function over time and to understand how these mechanisms go awry in aging and neurological disease. Our lab tackles these questions using a multidisciplinary approach that integrates biochemistry, single-cell genomics, cell biology, and neuronal circuit function.
Specific Projects in the Pollina Lab Include:
Role of Neuronal-Specific Chromatin Complexes 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 DNA double-stranded breaks. 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 neuronal cell types. Using mouse models, we are examining 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 epigenome 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.
Role of 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 shortens 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 epigenome integrity across neuronal ensembles in the brain and body, using both genomic techniques and behavioral assays.
Postdoctoral Training, Neurobiology, Harvard Medical School
PhD, Cancer Biology, Stanford University
Princeton in Asia International Teaching Fellow, Ngee Ann Polytechnic, Singapore
Bachelor of the Arts, Princeton University
- Pollina, E. A.*, Gilliam, D. T.*, Landau, A. T., Lin, C., Pajarillo, N., Davis, C. P., Harmin, D. A., Yap, E. L., Vogel, I. R., Griffith, E. C., Nagy, M. A., Ling, E., Duffy, E. E., Sabatini, B. L., Weitz, C. J. & Greenberg, M. E. A NPAS4-NuA4 complex couples synaptic activity to DNA repair. Nature, (2023). DOI: 10.1038/s41586-023-05711-7 *equal contribution
- Vaccaro, A.*, Kaplan Dor, Y.*, Nambara, K., Pollina, E. A., Lin, C., Greenberg, M. E. & Rogulja, D. Sleep Loss Can Cause Death through Accumulation of Reactive Oxygen Species in the Gut. Cell 181, 1307-1328 e1315, (2020). *equal contribution
- Sharma, N.*, Pollina, E. A.*, Nagy, M. A.*, Yap, E. L., DiBiase, F. A., Hrvatin, S., Hu, L., Lin, C. & Greenberg, M. E. ARNT2 Tunes Activity-Dependent Gene Expression through NCoR2 Mediated Repression and NPAS4-Mediated Activation. Neuron 102, 390-406 e399, (2019). *equal contribution
- Benayoun, B. A., Pollina, E. A., Singh, P. P., Mahmoudi, S., Harel, I., Casey, K. M., Dulken, B. W., Kundaje, A. & Brunet, A. Remodeling of epigenome and transcriptome landscapes with aging in mice reveals widespread induction of inflammatory responses. Genome Res 29, 697-709, (2019).
- Benayoun, B. A.*, Pollina, E. A.*, Ucar, D.*, Mahmoudi, S., Karra, K., Wong, E. D., Devarajan, K., Daugherty, A. C., Kundaje, A. B., Mancini, E., Hitz, B. C., Gupta, R., Rando, T. A., Baker, J. C., Snyder, M. P., Cherry, J. M. & Brunet, A. H3K4me3 breadth is linked to cell identity and transcriptional consistency. Cell 158, 673-688, (2014). *equal contribution
Pollina, E. A. & Brunet, A. Epigenetic regulation of aging stem cells. Oncogene 30,
Benayoun, B. A.*, Pollina, E. A.* & Brunet, A. Epigenetic regulation of ageing: linking
environmental inputs to genomic stability. Nat Rev Mol Cell Biol 16, 593-610, (2015).