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Alex Fiorenza: Exploring the Molecular Details of PARP1-Chromatin InteractionsÌý

ÌýChromatin structure and organization are essential for compacting DNA and maintaining genome integrity. Despite the protective role of chromatin, the genome undergoes approximately one million DNA lesions per cell per day.ÌýPoly(ADP-ribose) polymerase 1 (PARP1) is a highly abundant nuclear enzyme that contributes to both chromatin architecture and DNA damage response. Upon detecting DNA damage, PARP1 catalyzes the attachment of ADP-ribose onto histones, leading to nucleosome destabilization and the recruitment of DNA repair machinery to the damage site. Interestingly, PARP1 also promotes chromatin compaction by directly binding nucleosome arrays in the absence of DNA damage. Structural studies have elucidated how PARP1 recognizes DNA breaks by contacting exposed nitrogenous bases; however, such features are absent in undamaged chromatin, suggesting a distinct binding mode. The molecular basis of how PARP1 interacts with and compacts chromatin in the absence of DNA damage remains poorly understood. Here, we employ structural and biophysical approaches to investigate how PARP1 binds undamaged chromatin and alters the three-dimensional arrangement of nucleosomes.Ìý

Mika Nevo: Defining the Subunit-Specific Functions of the CCR4-NOT Complex in RNA RegulationÌý

The CCR4-NOT deadenylation complex regulates RNA stability and translation, but the contributions of the individual subunits remain poorly defined. We systematically depleted each core subunit in human cells and performed transcriptome wide profiling to identify genes affected by loss of specific components. By integrating gene expression changes with RNA features, including stability, translation efficiency, and codon usage, we uncovered patterns of subunit-specific regulation. Functional enrichment highlighted diverse biological processes affected by subunit depletion, including pathways related to cell cycle control. We also identified RNA binding proteins and sequence motifs associated with CNOT sensitivity. This study provides a comprehensive resource for understanding the modular post-transcriptional control by CCR4-NOT.Ìý

Colin Sempeck: Identifying microbes involved in human type 1 diabetes developmentÌý

Type-1 diabetes (T1D), is an autoimmune disease characterized by the destruction of pancreatic ß-cells, resulting in insulin production loss. T1D has a complex etiology comprised of both genetic and environmental components, such as the microbiome. T1D and other auto-immune diseases are increasing globally, which is a modern trend potentially resulting from the loss of beneficial microbes. We previously identified a specific timeframe where stool microbes from infants between 7-12 months old were uniquely able to promote ß-cell development in mice1. These stool samples came from The Environmental Determinants of Diabetes in the Young (TEDDY) study, a longitudinal cohort of ~800 diabetes prone participants from the US and Europe. We propose to computationally digest >10k TEDDY microbiome samples to identify microbial signatures associated with age, that may predict disease. We hypothesize that microbes capable of promoting ß-cells are enriched in healthy individuals, and that these signatures may differ across geographical locations, and antibiotic and breast milk usage.Ìý

Erin Taylor: ALT-ernative Chromatin Functions: Heterochromatin as a Driver of TelomereÌýÌý

MaintenanceÌýÌý

ÌýThe Alternative Lengthening of Telomeres (ALT) pathway is a recombination-mediated DNA synthesis mechanism used by certain cancers to maintain telomere length independent of telomerase. Although chromatin structure is known to influence recombination efficiency, the function of chromatin in ALT remains unclear as ALT telomeres paradoxically exhibit chromatin features consistent with both open, permissive chromatin and canonically repressive features—reduced nucleosome density alongside enrichment of heterochromatin-associated factors. To determine if heterochromatin enrichment observed at ALT telomeres functionally contributes to the pathway, we leveraged a molecular tethering approach to experimentally enrich heterochromatin at telomeres. Our data in ALT+ cells indicates that heterochromatin is not restrictive, nor permissive, but actively promotes ALT activity. We demonstrate that telomeric heterochromatin enrichment increases key ALT hallmarks, including ALT-associated PML body (APB) formation, C-circle accumulation, and telomeric DNA synthesis. Furthermore, we find that the direct tethering of the heterochromatin protein HP1α to the telomere-binding factor TRF1 is sufficient to drive APB formation and induce hallmarks of ALT activity in non-ALT cells. In contrast, recruitment of endogenous HP1a via local enrichment of H3K9me3 is not, unless the histone chaperone ATRX (mutated or dysregulated in the majority of ALT+ tumors) is suppressed. Together, our findings indicate that heterochromatin can act as a functional driver of ALT, likely by promoting telomere compartmentalization into PML nuclear bodies rather than altering nucleosome density.Ìý

Josh Fandel: TBD

Ashley Azadeh: TBD