Carbon Starvation Metabolically Regulates Chromatin for Transcriptome Rewiring

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dc.contributor.advisorConrad, Nicholasen
dc.contributor.committeeMemberKraus, W. Leeen
dc.contributor.committeeMemberOrth, Kimen
dc.contributor.committeeMemberTu, Benjaminen
dc.creatorHsieh, Wen-Chuanen
dc.creator.orcid0000-0001-9673-038X
dc.date.accessioned2024-06-07T19:19:39Z
dc.date.available2024-06-07T19:19:39Z
dc.date.created2022-05
dc.date.issued2022-05
dc.date.submittedMay 2022
dc.date.updated2024-06-07T19:19:40Z
dc.descriptionThe general metadata -- e.g., title, author, abstract, subject headings, etc. -- is publicly available, but access to the submitted files is restricted to UT Southwestern campus access and/or authorized UT Southwestern users.en
dc.description.abstractCells 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.en
dc.format.mimetypeapplication/pdfen
dc.identifier.oclc1438579284
dc.identifier.urihttps://hdl.handle.net/2152.5/10334
dc.language.isoenen
dc.subjectAcetyl Coenzyme Aen
dc.subjectGluconeogenesisen
dc.subjectGlucoseen
dc.subjectHistonesen
dc.subjectLipid Metabolismen
dc.subjectProtein Processing, Post-Translationalen
dc.subjectSaccharomyces cerevisiaeen
dc.titleCarbon Starvation Metabolically Regulates Chromatin for Transcriptome Rewiringen
dc.typeThesisen
dc.type.materialtexten
local.embargo.lift2024-06-01
local.embargo.terms2024-06-01
thesis.degree.departmentGraduate School of Biomedical Sciencesen
thesis.degree.disciplineBiological Chemistryen
thesis.degree.grantorUT Southwestern Medical Centeren
thesis.degree.levelDoctoralen
thesis.degree.nameDoctor of Philosophyen

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