Patrick A. Grant

Education

  • BS, University of Portsmouth, United Kingdom
  • PhD, Karolinska Institute, Stockholm, Sweden
  • Postdoc, HHMI, Pennsylvania State University, PA.

Primary Appointment

  • Associate Professor, Biochemistry and Molecular Genetics

Contact

Research Interest(s)

Transcription; Chromatin Modifications, Neurodegenerative Disease, Cancer

Research Description

In the eukaryotic cell nucleus, DNA is packaged by histones into nucleosomes, the repeating subunits of chromatin. This packaging of DNA strongly inhibits transcription, hampering the binding of transcriptional activators to their cognate DNA sites and inhibiting transcription elongation. A number of chromatin remodeling activities have been identified that assist transcriptional activators to overcome this barrier, by creating a localized alteration in chromatin strucutre. In addition to these activities the posttranslational acetylation of core histones has also been linked to the transcriptional capacity of chromatin for more than four decades. The acetylation of histones is catalyzed by histone acetyltransferases (HATs), which are often found to be associated with large multisubunit protein complexes that contain components with identity or homology to known regulators of transcription. In fact, a number of transcriptional coactivator proteins have now been identified as HATs, providing a direct molecular basis for the coupling of histone acetylation and transcriptional regulation. Why and how these proteins function as part of high molecular weight activities is not clearly understood however. Our research has primarily focused on the identification and characterization of native HAT/transcriptional adaptor activities from the budding yeast Saccharomyces cerevisiae and to study their role in transcriptional activation. We have isolated multiple complexes, including the conserved SAGA (Spt-Ada-Gcn5-Acetyltransferase) activity. Our research objectives deal with a structural and functional dissection of the components of SAGA and other related HAT complexes. This approach is designed to investigate the multifunctionality of these complexes in their specificity of acetylation, activator and basal factor interaction, promoter selectivity and transcriptional stimulation, in order to understand their relevance to and mechanism of gene activation. Our studies have expanded to the identification and characterization of other novel histone modifying complexes associated with cell cycle progression and gene expression. We are currently focused on a study of the regulation and function of a novel epigenome dedicated to protein biosynthesis and DNA replication and epigenetic mechanisms in cancer cells.

An important aspect of a number of related histone-modifying complexes has been the identification of an evolutionarily conserved components which have been directly linked to factors associated with certain cancers or neurodegenerative disease. This includes the Ataxin-7 protein within the SAGA complex, which undergoes polyglutamine expansion in the debilitating neurodegenerative disease Spinocerebellar Ataxia type 7. This discovery provides a new avenue of investigation into how certain disorders may arise. Therefore, a clear understanding of how histone-modifying complexes function is vital in order to understand their role in gene activation in health and disease.

Selected Publications

  • Burke T, Miller J, Grant P. Direct inhibition of Gcn5 protein catalytic activity by polyglutamine-expanded ataxin-7. The Journal of biological chemistry. 2013;288(47): 34266-75. PMID: 24129567 | PMCID: PMC3837167
  • McCullough S, Xu X, Dent S, Bekiranov S, Roeder R, Grant P. Reelin is a target of polyglutamine expanded ataxin-7 in human spinocerebellar ataxia type 7 (SCA7) astrocytes. Proceedings of the National Academy of Sciences of the United States of America. 2012;109(52): 21319-24. PMID: 23236151 | PMCID: PMC3535616
  • Miller J, Grant P. The role of DNA methylation and histone modifications in transcriptional regulation in humans. Sub-cellular biochemistry. 2012;61 289-317. PMID: 23150256
  • Bian C, Xu C, Ruan J, Lee K, Burke T, Tempel W, Barsyte D, Li J, Wu M, Zhou B, Fleharty B, Paulson A, Allali-Hassani A, Zhou J, Mer G, Grant P, Workman J, Zang J, Min J. Sgf29 binds histone H3K4me2/3 and is required for SAGA complex recruitment and histone H3 acetylation. The EMBO journal. 2011;30(14): 2829-42. PMID: 21685874 | PMCID: PMC3160252
  • Chen Y, Gatchel J, Lewis R, Mao C, Grant P, Zoghbi H, Dent S. Gcn5 loss-of-function accelerates cerebellar and retinal degeneration in a SCA7 mouse model. Human molecular genetics. 2011;21(2): 394-405. PMID: 22002997 | PMCID: PMC3276287
  • Gan Q, Thiébaud P, Thézé N, Jin L, Xu G, Grant P, Owens G. WD repeat-containing protein 5, a ubiquitously expressed histone methyltransferase adaptor protein, regulates smooth muscle cell-selective gene activation through interaction with pituitary homeobox 2. The Journal of biological chemistry. 2011;286(24): 21853-64. PMID: 21531708 | PMCID: PMC3122240
  • Lee K, Sardiu M, Swanson S, Gilmore J, Torok M, Grant P, Florens L, Workman J, Washburn M. Combinatorial depletion analysis to assemble the network architecture of the SAGA and ADA chromatin remodeling complexes. Molecular systems biology. 2011;7 503. PMID: 21734642 | PMCID: PMC3159981
  • Baker S, Phillips J, Anderson S, Qiu Q, Shabanowitz J, Smith M, Yates J, Hunt D, Grant P. Histone H3 Thr 45 phosphorylation is a replication-associated post-translational modification in S. cerevisiae. Nature cell biology. 2010;12(3): 294-8. PMID: 20139971 | PMCID: PMC2856316
  • Ding S, Fischer W, Kaparakis-Liaskos M, Liechti G, Merrell D, Grant P, Ferrero R, Crowe S, Haas R, Hatakeyama M, Goldberg J. Helicobacter pylori-induced histone modification, associated gene expression in gastric epithelial cells, and its implication in pathogenesis. PloS one. 2010;5(4): e9875. PMID: 20368982 | PMCID: PMC2848570
  • McCullough S, Grant P. Histone acetylation, acetyltransferases, and ataxia--alteration of histone acetylation and chromatin dynamics is implicated in the pathogenesis of polyglutamine-expansion disorders. Advances in protein chemistry and structural biology. 2010;79 165-203. PMID: 20621284 | PMCID: PMC2964930
  • Stolzenberg D, Grant P, Bekiranov S. Epigenetic methodologies for behavioral scientists. Hormones and behavior. 2010;59(3): 407-16. PMID: 20955712 | PMCID: PMC3093106
  • Tsai H, Grant P, Rissman E. Sex differences in histone modifications in the neonatal mouse brain. Epigenetics : official journal of the DNA Methylation Society. 2008;4(1): 47-53. PMID: 19029819 | PMCID: PMC2667098
  • Baker S, Grant P. The SAGA continues: expanding the cellular role of a transcriptional co-activator complex. Oncogene. 2007;26(37): 5329-40. PMID: 17694076 | PMCID: PMC2746020
  • Daniel J, Grant P. Multi-tasking on chromatin with the SAGA coactivator complexes. Mutation research. 2007;618(1): 135-48. PMID: 17337012 | PMCID: PMC1892243