Archaeal histones share a common ancestry with the histone-folds of the eukaryotic nucleosome cores histones and subunits of many large eukaryotic transcription factors. The histone fold is a structural motif that directs dimer formation, and archaeal histones form homodimers and heterodimers but eukaryotic histone folds now form only heterodimers. Archaeal histones also bind DNA and assemble into complexes spontaneously and individually, and can wrap DNA in either a negative or positive supercoil. They therefore provide a unique opportunity, and a practical experimental system to establish the molecular determinants of histone:histone and histone:DNA interactions. The experiments proposed will generate a detailed structural understanding of histone fold partner specificity, histone-DNA affinity, the positioning of histone assembly, and the determinants of the direction of DNA supercoiling. These are all issues of central and fundamental importance to understanding genome organization and the roles of histones and histone foldcontaining complexes in regulating gene expression in Eukaryotes, and in Archaea. The information gained will also be of importance in understanding how defects in these molecular assemblies and interactions negatively impact human development and health. We have established that different archaeal histone assemblies have sequence-dependent differences in DNA affinity, and this suggests an entirely novel concept for gene regulation based on alternative histone dimer assembly. Chromatin immunoprecipitation coupled with DNA microarray hybridization will be used to investigate this new idea, and to test the hypothesis that this archaeal histone regulatory system was the foundation for eukaryotic genome silencing and gene regulation by positioned nucleosome assembly.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM053185-10
Application #
7071826
Study Section
Special Emphasis Panel (ZRG1-MBC-2 (01))
Program Officer
Carter, Anthony D
Project Start
1995-09-01
Project End
2008-06-30
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
10
Fiscal Year
2006
Total Cost
$274,455
Indirect Cost
Name
Ohio State University
Department
Microbiology/Immun/Virology
Type
Schools of Arts and Sciences
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
Mattiroli, Francesca; Bhattacharyya, Sudipta; Dyer, Pamela N et al. (2017) Structure of histone-based chromatin in Archaea. Science 357:609-612
Pan, Miao; Santangelo, Thomas J; ?ubo?ová, Lubomíra et al. (2013) Thermococcus kodakarensis has two functional PCNA homologs but only one is required for viability. Extremophiles 17:453-61
Pan, Miao; Santangelo, Thomas J; Li, Zhuo et al. (2011) Thermococcus kodakarensis encodes three MCM homologs but only one is essential. Nucleic Acids Res 39:9671-80
Li, Zhuo; Pan, Miao; Santangelo, Thomas J et al. (2011) A novel DNA nuclease is stimulated by association with the GINS complex. Nucleic Acids Res 39:6114-23
Santangelo, Thomas J; Cubonova, L'ubomira; Reeve, John N (2011) Deletion of alternative pathways for reductant recycling in Thermococcus kodakarensis increases hydrogen production. Mol Microbiol 81:897-911
Santangelo, Thomas J; Reeve, John N (2010) Deletion of switch 3 results in an archaeal RNA polymerase that is defective in transcript elongation. J Biol Chem 285:23908-15
Li, Zhuo; Santangelo, Thomas J; Cubonova, L'ubomira et al. (2010) Affinity purification of an archaeal DNA replication protein network. MBio 1:
Santangelo, Thomas J; Cubonova, L'ubomira; Reeve, John N (2010) Thermococcus kodakarensis genetics: TK1827-encoded beta-glycosidase, new positive-selection protocol, and targeted and repetitive deletion technology. Appl Environ Microbiol 76:1044-52
Santangelo, Thomas J; Cubonová, L'ubomíra; Skinner, Katherine M et al. (2009) Archaeal intrinsic transcription termination in vivo. J Bacteriol 191:7102-8
Friedrich-Jahn, Ulrike; Aigner, Johanna; Langst, Gernot et al. (2009) Nanoarchaeal origin of histone H3? J Bacteriol 191:1092-6

Showing the most recent 10 out of 49 publications