The Science of Connections: Bridging Chromatin Folding, Synaptic Plasticity, and Neurophysiology
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Jennifer Phillips-Cremins, Ph.D.
Associate Professor of Genetics and Bioengineering
University of Pennsylvania The School of Engineering and Applied Sciences Department of Bioengineering
Jennifer E. Phillips-Cremins, Ph.D. is a tenured associate professor and Deans’ Faculty Fellow in Engineering and Medicine in the Departments of Genetics and Bioengineering at the University of Pennsylvania. During her Ph.D. candidacy at Georgia Institute of Technology, Dr. Cremins was funded by an NSF Graduate Research Fellowship to develop transcription factor-based genetic engineering strategies for the direct conversion of dermal fibroblasts into osteoblasts. She was then funded by an NIH F32 to conduct a unique multi-disciplinary postdoc in which she simultaneously pursued computational and molecular genomics training in the laboratories of Job Dekker and Victor Corces. In 2014, Dr. Cremins opened the Laboratory for Chromatin and Spatial Neurobiology at UPenn, where she leads an interdisciplinary team consisting of epigeneticists, neurobiologists, bioengineers, and computer scientists dedicated to understanding how chromatin works through long-range folding mechanisms to encode neuronal specification and synaptic plasticity in healthy and diseased neural circuits. The lab employs cutting-edge molecular and computational tools to understand (1) long-range chromatin mechanisms governing synaptic plasticity in healthy neurons and (2) how the 3D genome is miswired in neurological diseases with synaptic defects such as Alzheimer’s and fragile X syndrome. Cremins’s work led to her selection as a NYSCF Robertson Investigator, NIH New Innovator, Alfred P. Sloan Foundation Fellow, NSF CAREER awardee, CZI Neurodegenerative Disease research pairs awardee, two-time Kavli Frontiers of Science Fellow, NIH Pioneer awardee, and the recipient of the 2021 ISSCR Susan Lim Outstanding Investigator Award.
Dr. Cremins views mentoring as the most important part of her faculty mission, and she actively serves as a mentor to researchers across career stages at Penn and other institutions. In the lab’s first ten years, she trained >40 individuals. Currently, there are 18 trainees in the group: 4 postdocs, 6 PhD students, 3 MD/PhD students, 1 PhD rotation student, 1 technician, and 3 undergraduate scholars. Her mentees have won awards including the NSF GRFP, NIHF30, NIHF31, NIHR25, NIHT32, Blavatnik Family fellowship, NYSCF Druckenmiller fellowship, Michael S. Brown fellowship, and Goldwater scholarship. Two students have won UPenn’s PhD Thesis award. Of the 25 scientists who graduated from the lab since 2014, nearly all are active in academic research, industry research, and/or academic medicine. Cremins has a track record of serving as an energetic, engaged, and dedicated mentor who generously invests in her trainees over the long term with a mentor-for-life mentality.
Summary
The Cremins Laboratory works at the spatial biology-technology interface to investigate the structure-function relationship of connections in the brain across the scales of chromatin, synapses, and circuits in normal neurophysiology and in neurological disorders. We have thus far focused in the nucleus on creating kilobase-resolution maps of higher-order folding of the chromatin fiber and understanding how classic epigenetic modifications work through long-range connections to govern genome function in neurodevelopment. We have developed and applied new molecular and computational technologies to elucidate chromatin folding patterns at kilobase-resolution genome-wide, thus discovering that long-range looping interactions in cis and inter-chromosomal interactions in trans change substantially during neural lineage commitment, somatic cell reprogramming, activation of post-mitotic neural circuits, and in neurological disorders. We have demonstrated that cohesin-mediated loops are necessary for the establishment of new gene expression programs in post-mitotic neurons, including the upregulation of genes encoding axon guidance, dendritic spine morphology, and synaptic plasticity during neuron maturation in vivo as well as activity-dependent transcription during neural stimulation in vitro. We have also 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. Using fragile X syndrome as a natural perturbation, we have uncovered BREACHes (Beacons of Repeat Expansion Anchored by Contacting Heterochromatin) - rare inter-chromosomal interactions connecting heterochromatinized synaptic genes susceptible to repeat instability, thus providing early insight into the genome’s structure-function relationship. Here, I will present new unpublished data describing 3D genome miswiring in a human neuron model with rare familial Alzheimer’s mutations as well as the functional link among loops and activity-dependent gene expression during neural circuit activation in vitro and in vivo. The long-term goal of the Cremins lab is to elucidate how the genome’s structure-function relationship influences synaptic plasticity and neurophysiology during memory encoding and consolidation and how this goes awry in intractable neurological disorders.
Learning Objectives:
- Understand how chromatin works through long-range physical folding mechanisms to influence gene expression in normal neurophysiology and neural lineage commitment - learn about genome misfolding in neurological disorders and is linked to dysregulated gene expression
- Gain awareness of cutting edge tools in molecular and cellular brain science, such as molecular Chromosome-Conformation
- Capture sequencing technologies, single-cell imaging, optogenetics, genome engineering, and induced pluripotent stem cell differentiation to neurons/organoids
https://videocast.nih.gov/watch=55006
This page was last updated on Friday, September 13, 2024