The Monthly Seminar on Physical Genomics: Training Program Research Showcase

September 25th @ 12pm (Central U.S. Time)

Register for the Live Zoom: https://tinyurl.com/pr5nbkf3

1. Physical Genomics of the Ovary: Linking Mechanics to Follicle Activation

Evelynn Chen, PhD Student, (Driskill Graduate Program), Laronda Lab

Ovarian granulosa cells (GCs) undergo dynamic morphological and functional changes during follicle activation, but the mechanisms linking these changes to steroidogenic function remain poorly understood. We hypothesize that mechanical cues from the ovarian microenvironment regulate GC morphology and that nuclear deformation can directly influence steroidogenesis. To investigate this, bovine ovarian cortical tissue was partially enzymatically digested to reduce extracellular matrix (ECM) constraint, while human ovarian tissue was analyzed to characterize GC nuclear morphology across folliculogenesis. Primary bovine GCs were also cultured on engineered micropillar substrates that induce nuclear deformation, and estradiol secretion was measured. Partial ECM digestion reduced collagen content and increased the proportion of BrdU+ GCs in primordial and transitional follicles, suggesting that disruption of mechanical constraint promotes early follicle activation. GC nuclear eccentricity also decreased significantly during human follicle activation, from 0.90 ± 0.00008 in primordial follicles to 0.72 ± 0.0098 in primary follicles (p < 0.0001). Furthermore, GCs cultured on micropillar substrates exhibited measurable nuclear deformation and produced approximately 3.5-fold more estradiol than cells cultured on flat substrates. Together, these findings suggest that mechanical cues and nuclear architecture actively regulate GC activation and steroidogenic function. Ongoing studies will define how physical confinement alters chromatin organization and steroidogenic gene expression, providing mechanistic insight into ovarian function and informing strategies for fertility and hormone restoration.

2. Determining the Physical Constraints of 3D Chromatin Architecture on Co-Transcriptional Splicin

Eric Tong, PhD Student, (Driskill Graduate Program), Backman Lab

Alternative splicing is a crucial step to mRNA processing and gene expression, with aberrant splicing being a prominent feature of human disease, aging, and cancer. As most splicing in metazoans is co-transcriptional—occurring on nascent RNA still tethered to template DNA—local chromatin landscape has been established to influence splicing decisions. However, the relationship between supranucleosomal chromatin structure and co-transcriptional splicing remains largely unexplored. The characterization of physical chromatin domains in electron microscopy data on intact nuclei reveal packing properties such that DNA mass density radially decays from dense cores to loose peripheries. This theoretically sequesters large transcriptional machinery, euchromatic enzymes, and active regions of DNA to domain surfaces, whereas small heterochromatic enzymes and suppressed DNA may be packed into domain interiors. As the canonical spliceosome is roughly 3-9 orders of magnitude than the largest active transcriptional elements, would splice-specific features potentially display a geometric bias in their three-dimensional positioning within domains? Could this organization influence splicing outcome and fidelity? To investigate this, we developed a feature annotation method focused on measure spacing of elements in nascent long-read transcripts. Surprisingly, longer introns seemed to splice more efficiently than shorter introns. Hypothesizing that these longer introns display features of packing domain organization or spatial constraint, we found they were highly enriched for signatures of heterochromatic histone marks and chromatin contacts. To further measure geometric distances, we imaged exons separated by the hypothesized “packed” introns to measure their distance from each other as well as heterochromatin.

Sponsored by the Center for Physical Genomics and Engineering, the Cancer and Physical Sciences Program at the Robert H. Lurie Comprehensive Cancer Center, and NIH Grants T32GM142604 and U54CA268084

Cost: Free, registration required at:https://tinyurl.com/pr5nbkf3

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