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Recent Submissions

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Carbon Starvation Metabolically Regulates Chromatin for Transcriptome Rewiring
(2022-05) Hsieh, Wen-Chuan; Conrad, Nicholas; Kraus, W. Lee; Orth, Kim; Tu, Benjamin
Cells robustly rewire their transcriptomes to survive under stress conditions. Yet, how does such reprogramming of gene expression occur? Under favorable nutrient conditions, acetyl-CoA normally promotes histone acetylation to activate genes required for cell growth. However, glucose starvation significantly reduces the availability of acetyl-CoA. And it is unclear how such a change impacts genome-wide histone acetylation and gene expression. In this study, I set up a robust glucose starvation model in budding yeast to discover a mechanism by which cells preserve acetyl-CoA, a key intermediate in energy metabolism, in order to sustain histone acetylation for gene activation even under stress conditions. I demonstrate a dramatic redistribution of histone acetylation upon glucose starvation. Mechanistically, I determined that a major histone deacetylase (HDAC) releases acetyl groups from histones at growth-promoting genes, which can subsequently be used to acetylate histones at a distinctive set of stress-responsive genes. Strikingly, bioinformatic analysis revealed these genes to be required for gluconeogenic and fat metabolism, which are metabolic pathways that generate acetyl-CoA for oxidation and ATP synthesis. Genetic deletion of histone modifiers mediating this reallocation, including the key HDAC or histone acetyltransferase (HAT), disrupts proper transcriptome rewiring for survival. Given the importance of acetate for recycling the acetyl- group, I next characterize acetyl-CoA synthetases (Acs), metabolic enzymes that convert acetate to acetyl-CoA. I demonstrate that Acs2 is required for maintaining global histone acetylation, yet its nuclear localization appears to be dispensable for such regulation. I observe that the catalytic activity of Acs2 governs the intracellular acetyl-CoA level and global histone acetylation amounts. Compromising its activity leads to up-regulation of ergosterol biosynthetic pathways in addition to gluconeogenic and fat metabolism genes upon glucose starvation. In summary, I reveal an unexpected switch in the specificity of histone acetylation to promote pathways that generate acetyl-CoA for oxidation when acetyl-CoA is limiting. I have elucidated how transcriptome rewiring is driven by reallocation of histone acetylation. My findings present a mechanism by which cells recycle acetyl groups to differentially acetylate histones for activation of key genes required for metabolism and survival.
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Improving Intra-Operative Parathyroid Hormone Result Times at the University Hospitals
(2022-05) Wang, Virginia Y.; Reed, W. Gary; Nwariaku, Fiemu; Holt, Shelby A.
Intra-operative parathyroid hormone (ioPTH) levels are the current gold standard for assessing completeness of resection in parathyroidectomy surgery. Due to the time-sensitive nature of these results, delays in processing ioPTH samples lead to non-value-added time (NVAT) in the operating room, which generates unnecessary financial burdens and potential safety hazards for both patients and the hospital system. Baseline analysis of data from 191 parathyroidectomy cases performed by the UT Southwestern Endocrine Surgery Group at Clements University Hospital (CUH) and the Outpatient Surgery Center (OSC) between September 2020 and April 2021 identified a statistically significant delay in the sample-to-lab interval time in cases at the OSC (mean of 27 minutes) compared to cases at CUH (mean of 8 minutes). The need for a lab courier at the OSC is likely a major contributor to this NVAT, as the OSC does not have an in-house lab. Though altering the lab infrastructure to make in-house ioPTH processing at the OSC would be the most effective way to equalize the delay, it was also infeasible within the time constraints of this project given the depth of high-level decision-making this would necessitate. I chose to focus instead on optimizing parathyroidectomy case preparation. I worked with CUH OR nursing clinical leads to modify the Epic template text of surgeon preference cards, which OR nursing staff use to prepare for cases. Analysis of pre- and post-change data from 43 parathyroidectomy cases performed in February and March of 2022 at CUH revealed post-change special cause variation in both the sample-to-lab and lab-to-result interval times. Moving forward, many other interventions are available to continue to improve team communication and knowledge sharing and protocolize contingency plans; further work also remains to be done to address logistical constraints at the OSC on an institutional level.