{"id":1731099,"date":"2025-06-17T11:18:32","date_gmt":"2025-06-17T15:18:32","guid":{"rendered":"https:\/\/med.virginia.edu\/faculty\/faculty-listing\/jss5y\/"},"modified":"2026-03-20T06:31:13","modified_gmt":"2026-03-20T10:31:13","slug":"jss5y","status":"publish","type":"faculty-listing","link":"https:\/\/med.virginia.edu\/faculty\/faculty-listing\/jss5y\/","title":{"rendered":"Smith, Jeffrey S."},"content":{"rendered":"<p><strong>Transcriptional silencing<\/strong>&#013;&#010;Understanding  how chromatin structure influences DNA-mediated processes has become a  fundamental problem in cellular biology. Chromatin is known to influence the  regulation of eukaryotic gene expression, DNA replication, DNA repair, and  recombination. Chromatin effects on gene expression can be either localized  (gene-specific) or more regional. The classic example of a regional chromatin  effect is silencing, the epigenetic transcriptional repression of large  heterochromatic chromosomal loci. Regions of silent chromatin in the budding  yeast <em>Saccharomyces cerevisiae<\/em> include the <em>HML<\/em> and <em>HMR<\/em> cryptic mating-type loci, telomeres,  and the ribosomal DNA (rDNA). Silencing at each of these loci requires the <u>S<\/u>ilent <u>I<\/u>nformation <u>R<\/u>egulator <u>2<\/u> (<em>SIR2<\/em>) gene, which encodes the founding member of a large,  phylogenetically conserved family of NAD+-dependent protein  deacetylases known as the Sirtuins. Sir2 is recruited to the silenced loci in  yeast through interactions with other proteins that bind to specific cis-acting  silencer elements. Once recruited to chromatin, Sir2 deacetylates lysines on  the N-terminal tails of histones H3 and H4, a critical step in the formation of  silent chromatin.&#013;&#010;One  of the research projects in our lab is to dissect the mechanism of silencing at  the yeast rDNA locus, which was originally defined as the <em>SIR2<\/em>-dependent repression of Pol II-transcribed reporter genes  positioned within the rDNA tandem array. More recently, <em>SIR2<\/em> was also found to silence the transcription of endogenous Pol  II-transcribed genes and non-coding RNAs embedded in the rDNA. The silent  chromatin structure set up by Sir2 also plays a role in suppressing  recombination between the rDNA repeats. Interestingly, transcription of the  rDNA genes by Pol I (the classic function of the rDNA is to produce rRNA for  ribosomes) is required for silencing of Pol II transcription. We are using  genetic and biochemical approaches aimed at 1) determining how Pol I  transcription promotes silencing of Pol II genes at the rDNA, 2) identifying  new genes that function in rDNA silencing, and 3) using rDNA silencing as a  model for the study of heterochromatin spreading and boundary element function.  In a related project, the lab has been investigating how chromatin modifying  enzymes and rDNA chromatin structure, in turn, regulate Pol I-mediated  transcription of the rDNA genes. Regulation of rDNA transcription has important  implications for diseases such as cancer and cardiac hypertrophy, both of which  involve uncontrolled cell growth and require high ribosome translational  capacity.&#013;&#010;<strong>NAD+ biosynthesis and the regulation of Sirtuins<\/strong>&#013;&#010;Sir2 and the other Sirtuins are  protein deacetylases that hydrolyze NAD+ as part of their catalytic  mechanism. For every deacetylation reaction, one molecule of NAD+ is  consumed. The byproducts are nicotinamide and 2&#8242;-O-acetyl-ADP ribose, with  nicotinamide acting as a strong feedback inhibitor of the reaction. To prevent  nicotinamide accumulation and Sirtuin inhibition, yeast cells recycle it into  NAD+ though a salvage pathway. This salvage pathway is critical not  only for detoxifying the nicotinamide, but to also maintain a cellular NAD+  concentration that is sufficiently high to promote silencing and other  Sirtuin-mediated processes. Another area of research in the lab is focused on  genetically elucidating new components of the NAD+ biosynthesis and  salvage pathways, and determining how they impact on silencing and other  Sirtuin regulated processes in yeast such as aging (see below) and thiamine  biosynthesis. Information gained from the yeast system is then used as a guide  for the investigation of Sirtuin biology in mammalian cells. This is critical  because mammalian Sirtuins have been implicated in the regulation of  aging-associated diseases including diabetes, cancer, and forms of  neurodegeneration.&#013;&#010;<strong>Yeast as a model system for aging and caloric restriction<\/strong>&#013;&#010;Caloric restriction (CR) is a  dietary regiment that extends the lifespan of almost every eukaryotic organism  that has been tested, including <em>Saccharomyces  cerevisiae<\/em>. To calorie restrict yeast, we simply reduce the glucose  concentration in the growth medium from 2% to 0.5%. This change is sufficient  to extend both the replicative lifespan (RLS) and chronological lifespan (CLS)  of this organism, where RLS is the number of times that a mother cell divides,  and CLS is the number of days that a non-dividing cell remains viable. <em>SIR2<\/em> is required for maintaining  replicative longevity via its role in controlling rDNA recombination, but is  not required for maintaining chronological longevity. We have therefore been  utilizing yeast genetics and genomics tools to identify novel genes and  cellular pathways that are involved in the control of chronological aging,  especially those that are required for the lifespan-extending effects of CR.  Such genes and pathways that are conserved in mammals have the potential to be  targets for therapeutics in the treatment of age-associated diseases.<\/p>\n","protected":false},"featured_media":1734210,"template":"","meta":{"_acf_changed":false,"inline_featured_image":false,"_links_to":"","_links_to_target":""},"otheraff":[2421,2409],"phd-degree":[2564],"primary":[2328],"research-discipline":[2487,2496,2489,2499,2490],"research-opportunity":[2540,2550,2548,2542,2543],"training-grant":[2310,2312,2315],"class_list":["post-1731099","faculty-listing","type-faculty-listing","status-publish","has-post-thumbnail","hentry","otheraff-cancer-center","otheraff-mstp","phd-degree-phd-biochemistryandmoleculargenetics","primary-biochemistry-and-molecular-genetics","research-discipline-biochemistry","research-discipline-epigenetics","research-discipline-genetics","research-discipline-metabolism","research-discipline-molecular-biology","research-opportunity-ro-biochemistry","research-opportunity-ro-cellularandmolecularmetabolism","research-opportunity-ro-epigenetics","research-opportunity-ro-genetics","research-opportunity-ro-molecularbiology","training-grant-cancer-research-training-in-molecular-biology","training-grant-training-in-cell-and-molecular-biology","training-grant-training-in-the-pharmacological-sciences"],"acf":[],"yoast_head":"<!-- This site is optimized with the Yoast SEO plugin v27.4 - https:\/\/yoast.com\/product\/yoast-seo-wordpress\/ -->\n<title>Smith, Jeffrey S. - Research Faculty Directory<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/med.virginia.edu\/faculty\/faculty-listing\/jss5y\/\" \/>\n<meta property=\"og:locale\" content=\"en_US\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Smith, Jeffrey S. - Research Faculty Directory\" \/>\n<meta property=\"og:description\" content=\"Transcriptional silencing&#013;&#010;Understanding how chromatin structure influences DNA-mediated processes has become a fundamental problem in cellular biology. 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