Jennifer E. Phillips-Cremins, Ph.D.
University of Pennsylvania
The School of Engineering and Applied Sciences
Department of Bioengineering
Lab: 515 Skirkanich Hall
Office: 304 Hayden Hall
210 South 33rd Street
Philadelphia, PA 19104
The Cremins Lab focuses on higher-order genome folding and how chromatin works through long-range, spatial mechanisms to govern neural specification and synaptic plasticity in healthy and diseased neural circuits. We have developed molecular and computational technologies to create kilobase-resolution maps of chromatin folding and have built synthetic architectural proteins to engineer loops with light, together catalyzing new understanding of the genome’s structure-function relationship. We applied our technologies to discover that topologically associating domains (TADs), nested subTADs, and loops undergo marked reconfiguration during neural lineage commitment, somatic cell reprogramming, neuronal activity stimulation, and in models of repeat expansion disorders. We have demonstrated that loops induced by neural circuit activation, engineered through synthetic architectural proteins, and miswired in fragile X syndrome (FXS) are tightly connected to transcription, thus providing early insight into the genome’s structure-function relationship. Moreover, we have also demonstrated that cohesin-mediated loop extrusion can position the location of human replication origins which fire in early S phase, revealing a role for genome structure beyond gene expression in DNA replication. Recently, we have discovered that nearly all unstable short tandem repeat tracts in trinucleotide expansion disorders are localized to the boundaries between TADs, suggesting they are hotspots for pathological instability. We have identified that Mb-scale H3K9me3 domains decorating autosomes and the X chromosome in FXS are exquisitely sensitive to the length of the CGG STR tract. H3K9me3 domains spatially connect via inter-chromosomal interactions to silence synaptic genes and stabilize STRs prone to instability on autosomes. Together, our work uncovers a link between subMegabase-scale genome folding and genome function in the mammalian brain, thus providing the foundation upon which we will dissect the functional role for chromatin mechanisms in governing defects in synaptic plasticity and long-term memory in currently intractable and poorly understood neurological disorders.
The Cremins lab aims to understand how chromatin works through long-range physical folding mechanisms to encode neuronal specification and long-term synaptic plasticity in healthy and diseased neural circuits. We pursue a multi-disciplinary approach integrating data across biological scales in the brain, including molecular Chromosome-Conformation-Capture sequencing technologies, single-cell imaging, optogenetics, genome engineering, induced pluripotent stem cell differentiation to neurons/organoids, and in vitro and in vivo electrophysiological measurements.
Our long-term scientific goal is to dissect the fundamental mechanisms by which chromatin architecture causally governs genome function and, ultimately, long-term synaptic plasticity and neural circuit features in healthy mammalian brains as well as during the onset and progression of neurodegenerative and neurodevelopmental disease states
Our long-term mentorship goal is to develop a diverse cohort of next-generation scientific thinkers and leaders cross-trained in molecular and computational approaches. We seek to create a positive, high-energy environment with open and honest communication to empower individuals to discover and refine their purpose and grow into the best versions of themselves.