Abstract:
Persistent DNA double-strand breaks (DSBs) in neurons are an early pathological hallmark of neurodegenerative diseases including Alzheimer’s Disease (AD) with the potential to disrupt genome integrity. We show increased chromosomal structural variations and mosaic gene fusions in neurons burdened with DSBs in the CK-p25 inducible mouse model of neurodegeneration. Next, we used single-nucleus RNA-seq in human post-mortem prefrontal cortex samples and found that excitatory neurons in AD were enriched for gene fusions. Gene fusions were particularly enriched in excitatory neurons with senescence and DNA repair gene signatures. Neurons burdened with DSBs also had elevated levels of cohesin along with progressive multiscale disruption of the 3D genome organization aligned with transcriptional changes in synaptic, neuronal development, and histone genes. Overall, this work demonstrates the disruption of genome stability and the 3D genome organization by DSBs in neurons as pathological steps in the progression of neurodegenerative diseases. Building upon this work, my future research program will explore the genomic and epigenetic disruptions and the 3D genome organization changes underlying neurodegeneration and brain aging in the cellular milieu of the brain.

Bio:
Vishnu Dileep is an NIH K99 postdoctoral fellow at The Picower Institute for Learning and Memory at MIT in the lab of Li-Huei Tsai. He completed his bachelor's in biotechnology from Vellore Institute of Technology, India, and later earned his Ph.D. in Cell and Molecular Biology from Florida State University, USA. Vishnu’s research program aims to understand the molecular basis of brain function and dysfunction through the lens of chromatin organization and epigenetics. His research particularly focuses on the genome and chromatin-level changes that mediate neurodegeneration and brain aging