Jeffrey S. Smith

Professor, Biochemistry and Molecular Genetics

Primary Location

1340 JPA Pinn Hall Room 6229A
PO Box 800733
Charlottesville, VA 22908

Primary Phone Number

434.243.5864

Fax Number

434.924.5069

[email protected]

Bio & Overview

Transcriptional silencing 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 Saccharomyces cerevisiae include the HML and HMR cryptic mating-type loci, telomeres, and the ribosomal DNA (rDNA). Silencing at each of these loci requires the Silent Information Regulator 2 (SIR2) 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. 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 SIR2-dependent repression of Pol II-transcribed reporter genes positioned within the rDNA tandem array. More recently, SIR2 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. NAD+ biosynthesis and the regulation of Sirtuins 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'-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. Yeast as a model system for aging and caloric restriction Caloric restriction (CR) is a dietary regiment that extends the lifespan of almost every eukaryotic organism that has been tested, including Saccharomyces cerevisiae. 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. SIR2 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.

Academic Information

Department: Biochemistry and Molecular Genetics

Academic Title: Professor

Primary Education

BS, Marine Biology, LIU/ Southampton Campus, Southampton, NY, 1989
PhD, Biochemistry, University of Medicine and Dentistry/ RWJMS, 1994
Postdoc, Molecular Biology, Johns Hopkins School of Medicine, 1999

Other Appointments

Associate Professor, MII
Associate Professor, BMBG
Associate Professor, MCDB

Other Affiliations

Member, Cancer Center
Member, Molecular Genetics and Epigenetics Program
MSTP
Professor, BIMS

Research Interests

Transcriptional Silencing and Aging in Yeast

Research Disciplines

Biochemistry
Epigenetics
Genetics
Metabolism
Molecular Biology

Research Opportunities

Biochemistry
Cellular and Molecular Metabolism
Epigenetics
Genetics
Molecular Biology

PhD Programs

Biochemistry & Molecular Genetics

Selected Publications

2023

Dinda, M., Fine, R. D., Saha, S., Wang, Z., Zang, C., Li, M., & Smith, J. S. (2023). Fob1-dependent condensin recruitment and loop extrusion on yeast chromosome III. PLOS GENETICS, 19(4). doi:10.1371/journal.pgen.1010705

2022

Smith, J. S. (2022). The long and short of rDNA and yeast replicative aging. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 119(23). doi:10.1073/pnas.2205124119

2020

Enriquez-Hesles, E., Smith, D. L., Maqani, N., Wierman, M. B., Sutcliffe, M. D., Fine, R. D., . . . Smith, J. S. (2020). A cell-nonautonomous mechanism of yeast chronological aging regulated by caloric restriction and one-carbon metabolism.. The Journal of biological chemistry, 296, 100125. doi:10.1074/jbc.ra120.015402

Enriquez-Hesles, E., Smith, D. L. J., Maqani, N., Wierman, M. B., Sutcliffe, M. D., Fine, R. D., . . . Smith, J. S. (2021). A cell-nonautonomous mechanism of yeast chronological aging regulated by caloric restriction and one-carbon metabolism. JOURNAL OF BIOLOGICAL CHEMISTRY, 296. doi:10.1074/jbc.RA120.015402

2019

Li, M., Fine, R. D., Dinda, M., Bekiranov, S., & Smith, J. S. (2019). A Sir2-regulated locus control region in the recombination enhancer of Saccharomyces cerevisiae specifies chromosome III structure. PLOS GENETICS, 15(8). doi:10.1371/journal.pgen.1008339

Fine, R. D., Maqani, N., Li, M., Franck, E., & Smith, J. S. (2019). Depletion of Limiting rDNA Structural Complexes Triggers Chromosomal Instability and Replicative Aging of Saccharomyces cerevisiae. GENETICS, 212(1), 75-91. doi:10.1534/genetics.119.302047

2018

Maqani, N., Fine, R. D., Shahid, M., Li, M., Enriquez-Hesles, E., & Smith, J. S. (2018). Spontaneous mutations in CYC8 and MIG1 suppress the short chronological lifespan of budding yeast lacking SNF1/AMPK. MICROBIAL CELL, 5(5), 233-248. doi:10.15698/mic2018.05.630

Fine, R., Maqani, N., Li, M., Franck, E., & Smith, J. (2018). Depletion of limiting rDNA structural complexes triggers chromosomal instability and replicative aging ofSaccharomyces cerevisiae. doi:10.1101/380675

Kharel, Y., Agah, S., Huang, T., Mendelson, A. J., Eletu, O. T., Barkey-Bircannl, P., . . . Lynch, K. R. (2018). Saccharomyces cerevisiae as a platform for assessing sphingolipid lipid kinase inhibitors. PLOS ONE, 13(4). doi:10.1371/journal.pone.0192179

2017

Wierman, M. B., Maqani, N., Strickler, E., Li, M., & Smith, J. S. (2017). Caloric Restriction Extends Yeast Chronological Life Span by Optimizing the Snf1 (AMPK) Signaling Pathway. MOLECULAR AND CELLULAR BIOLOGY, 37(13). doi:10.1128/MCB.00562-16

Kharel, Y., Agah, S., Huang, T., Mendelson, A., Eletu, O., Barkey-Bircann, P., . . . Lynch, K. (2017). Saccharomyces cerevisiaeas a Platform for Assessing Sphingolipid Lipid Kinase Inhibitors. doi:10.1101/148858

2016

Gartenberg, M. R., & Smith, J. S. (2016). The Nuts and Bolts of Transcriptionally Silent Chromatin in Saccharomyces cerevisiae. GENETICS, 203(4), 1563-+. doi:10.1534/genetics.112.145243

Buck, S. W., Maqani, N., Matecic, M., Hontz, R. D., Fine, R. D., Li, M., & Smith, J. S. (2016). RNA Polymerase I and Fob1 contributions to transcriptional silencing at the yeast rDNA locus. NUCLEIC ACIDS RESEARCH, 44(13), 6173-6184. doi:10.1093/nar/gkw212

2015

Wierman, M. B., Matecic, M., Valsakumar, V., Li, M., Smith, D. L. J., Bekiranov, S., & Smith, J. S. (2015). Functional genomic analysis reveals overlapping and distinct features of chronologically long-lived yeast populations. AGING-US, 7(3), 177-194. doi:10.18632/aging.100729

2014

Johnson, J. M., Smith, J. S., & Schneider, D. A. (2014). A User's Guide to the Ribosomal DNA in Saccharomyces cerevisiae. YEAST GENETICS: METHODS AND PROTOCOLS, 1205, 303-328. doi:10.1007/978-1-4939-1363-3_18

2013

Kenwood, B. M., Weaver, J. L., Bajwa, A., Poon, I. K., Byrne, F. L., Murrow, B. A., . . . Hoehn, K. L. (2014). Identification of a novel mitochondria! uncoupler that does not depolarize the plasma membrane. MOLECULAR METABOLISM, 3(2), 114-123. doi:10.1016/j.molmet.2013.11.005

Wierman, M. B., & Smith, J. S. (2014). Yeast sirtuins and the regulation of aging. FEMS YEAST RESEARCH, 14(1), 73-88. doi:10.1111/1567-1364.12115

Yang, J. H., Polanowska-Grabowska, R. K., Smith, J. S., Shields, C. W., & Saucerman, J. J. (2014). PKA catalytic subunit compartmentation regulates contractile and hypertrophic responses to β-adrenergic signaling. JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, 66, 83-93. doi:10.1016/j.yjmcc.2013.11.001

Li, M., Valsakumar, V., Poorey, K., Bekiranov, S., & Smith, J. S. (2013). Genome-wide analysis of functional sirtuin chromatin targets in yeast. GENOME BIOLOGY, 14(5). doi:10.1186/gb-2013-14-5-r48

Johnson, J. M., French, S. L., Osheim, Y. N., Li, M., Hall, L., Beyer, A. L., & Smith, J. S. (2013). Rpd3-and Spt16-Mediated Nucleosome Assembly and Transcriptional Regulation on Yeast Ribosomal DNA Genes. MOLECULAR AND CELLULAR BIOLOGY, 33(14), 2748-2759. doi:10.1128/MCB.00112-13

2012

McClure, J. M., Wierman, M. B., Maqani, N., & Smith, J. S. (2012). Isonicotinamide Enhances Sir2 Protein-mediated Silencing and Longevity in Yeast by Raising Intracellular NAD⁺ Concentration. JOURNAL OF BIOLOGICAL CHEMISTRY, 287(25), 20957-20966. doi:10.1074/jbc.M112.367524

2010

French, S. L., Sikes, M. L., Hontz, R. D., Osheim, Y. N., Lambert, T. E., El Hage, A., . . . Beyer, A. L. (2011). Distinguishing the Roles of Topoisomerases I and II in Relief of Transcription-Induced Torsional Stress in Yeast rRNA Genes. MOLECULAR AND CELLULAR BIOLOGY, 31(3), 482-494. doi:10.1128/MCB.00589-10

Li, M., Petteys, B. J., McClure, J. M., Valsakumar, V., Bekiranov, S., Frank, E. L., & Smith, J. S. (2010). Thiamine Biosynthesis in Saccharomyces cerevisiae Is Regulated by the NAD⁺- Dependent Histone Deacetylase Hst1. MOLECULAR AND CELLULAR BIOLOGY, 30(13), 3329-3341. doi:10.1128/MCB.01590-09

Matecic, M., Smith, D. L. J., Pan, X., Maqani, N., Bekiranov, S., Boeke, J. D., & Smith, J. S. (2010). A Microarray-Based Genetic Screen for Yeast Chronological Aging Factors. PLOS GENETICS, 6(4). doi:10.1371/journal.pgen.1000921