3D genome folding, unfolding, and refolding in the mammalian brain

Dr Jennifer E. Phillips-Cremins

The Penn Epigenetics Institute
Perelman School of Medicine
University of Pennsylvania, Philadelphia USA

 

The Cremins Lab focuses on higher-order genome folding and how classic epigenetic modifications work through long-range, spatial mechanisms to govern synaptic plasticity in healthy and diseased neural circuits. Much is already known regarding how transcription factors work in the context of the linear genome to regulate brain development. Yet, severe limitations exist in our ability to engineer chromatin in neural circuits to correct synaptic defects in vivo. At the lab’s inception, it remained unclear whether and how genome folding could functionally influence cell type-specific gene expression. We have developed and applied new molecular and computational technologies to discover that nested subTADs and long-range loops undergo marked reconfiguration during neural lineage commitment, somatic cell reprogramming, neuronal activity stimulation, and in repeat expansion disorders. We demonstrated that loops induced by neural circuit activation, engineered through synthetic architectural proteins, and miswired in fragile X syndrome were tightly connected to transcription, thus providing early insight into the genome’s structure-function relationship. We are currently focused on understanding how, when, and why 3D genome folding patterns contribute to synaptic plasticity and dysfunction in neural circuits. Addressing this knowledge gap will provide an essential foundation for our long-term goal to engineer the 3D genome to reverse pathologic synaptic defects in debilitating neurological diseases.

Jennifer Phillips-Cremins, Ph.D. is an Associate Professor and Deans' Faculty Fellow in Engineering and Medicine at the University of Pennsylvania with primary appointments in the Departments of Bioengineering and Genetics. Dr. Cremins obtained her Ph.D. in Biomedical Engineering from the Georgia Institute of Technology in the laboratory of Andres Garcia. She then conducted a multi-disciplinary postdoc in the laboratories of Job Dekker and Victor Corces. Dr. Cremins now runs the Chromatin Architecture and Systems Neurobiology laboratory at UPenn. Her primary research interests lie in understanding the long-range chromatin architecture mechanisms that govern neural specification and synaptic plasticity in healthy neurons and how these epigenetic mechanisms go awry in neurodevelopmental and neurodegenerative diseases. She has been selected as a 2014 New York Stem Cell Foundation Robertson Investigator, a 2015 Albert P. Sloan Foundation Fellow, a 2016 and 2018 Kavli Frontiers of Science Fellow, 2015 NIH Director's New Innovator Awardee, 2020 NSF CAREER Awardee, and a 2020 CZI Neurodegenerative Disease Pairs Awardee.

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