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Grant, Patrick

Patrick Grant

Primary Appointment

Biochemistry and Molecular Genetics

Contact Information

PO Box 800733
Charlottesville, VA 22908
Telephone: 434-243-5766
Fax: 434-924-5069
Email: pag9n@virginia.edu

Research Interests

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

Lan X, Koutelou E, Schibler AC, Chen YC, Grant PA, Dent SY, Poly(Q) Expansions in ATXN7 Affect Solubility but Not Activity of the SAGA Deubiquitinating Module., 2015; Molecular and cellular biology. 35(10) 1777-87 PMID: 25755283 | PMCID: PMC4405643

Burke TL, Miller JL, Grant PA, Direct inhibition of Gcn5 protein catalytic activity by polyglutamine-expanded ataxin-7., 2013; The Journal of biological chemistry. 288(47) 34266-75 PMID: 24129567 | PMCID: PMC3837167

McCullough SD, Xu X, Dent SY, Bekiranov S, Roeder RG, Grant PA, Reelin is a target of polyglutamine expanded ataxin-7 in human spinocerebellar ataxia type 7 (SCA7) astrocytes., 2012; Proceedings of the National Academy of Sciences of the United States of America. 109(52) 21319-24 PMID: 23236151 | PMCID: PMC3535616

Miller JL, Grant PA, The role of DNA methylation and histone modifications in transcriptional regulation in humans., 2012; Sub-cellular biochemistry. 61() 289-317 PMID: 23150256 |

Chen YC, Gatchel JR, Lewis RW, Mao CA, Grant PA, Zoghbi HY, Dent SY, Gcn5 loss-of-function accelerates cerebellar and retinal degeneration in a SCA7 mouse model., 2011; Human molecular genetics. 21(2) 394-405 PMID: 22002997 | PMCID: PMC3276287

Lee KK, Sardiu ME, Swanson SK, Gilmore JM, Torok M, Grant PA, Florens L, Workman JL, Washburn MP, Combinatorial depletion analysis to assemble the network architecture of the SAGA and ADA chromatin remodeling complexes., 2011; Molecular systems biology. 7() 503 PMID: 21734642 | PMCID: PMC3159981

Bian C, Xu C, Ruan J, Lee KK, Burke TL, Tempel W, Barsyte D, Li J, Wu M, Zhou BO, Fleharty BE, Paulson A, Allali-Hassani A, Zhou JQ, Mer G, Grant PA, Workman JL, Zang J, Min J, Sgf29 binds histone H3K4me2/3 and is required for SAGA complex recruitment and histone H3 acetylation., 2011; The EMBO journal. 30(14) 2829-42 PMID: 21685874 | PMCID: PMC3160252

Gan Q, Thi?baud P, Th?z? N, Jin L, Xu G, Grant P, Owens GK, 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., 2011; The Journal of biological chemistry. 286(24) 21853-64 PMID: 21531708 | PMCID: PMC3122240

Baker SP, Phillips J, Anderson S, Qiu Q, Shabanowitz J, Smith MM, Yates JR, Hunt DF, Grant PA, Histone H3 Thr 45 phosphorylation is a replication-associated post-translational modification in S. cerevisiae., 2010; Nature cell biology. 12(3) 294-8 PMID: 20139971 | PMCID: PMC2856316

Stolzenberg DS, Grant PA, Bekiranov S, Epigenetic methodologies for behavioral scientists., 2010; Hormones and behavior. 59(3) 407-16 PMID: 20955712 | PMCID: PMC3093106

McCullough SD, Grant PA, Histone acetylation, acetyltransferases, and ataxia--alteration of histone acetylation and chromatin dynamics is implicated in the pathogenesis of polyglutamine-expansion disorders., 2010; Advances in protein chemistry and structural biology. 79() 165-203 PMID: 20621284 | PMCID: PMC2964930

Ding SZ, Fischer W, Kaparakis-Liaskos M, Liechti G, Merrell DS, Grant PA, Ferrero RL, Crowe SE, Haas R, Hatakeyama M, Goldberg JB, Helicobacter pylori-induced histone modification, associated gene expression in gastric epithelial cells, and its implication in pathogenesis., 2010; PloS one. 5(4) e9875 PMID: 20368982 | PMCID: PMC2848570

Tsai HW, Grant PA, Rissman EF, Sex differences in histone modifications in the neonatal mouse brain., 2008; Epigenetics : official journal of the DNA Methylation Society. 4(1) 47-53 PMID: 19029819 | PMCID: PMC2667098

Baker SP, Grant PA, The SAGA continues: expanding the cellular role of a transcriptional co-activator complex., 2007; Oncogene. 26(37) 5329-40 PMID: 17694076 | PMCID: PMC2746020

Daniel JA, Grant PA, Multi-tasking on chromatin with the SAGA coactivator complexes., 2007; Mutation research. 618(1) 135-48 PMID: 17337012 | PMCID: PMC1892243

Torok MS, Grant PA, The generation and recognition of histone methylation., 2006; Results and problems in cell differentiation. 41() 25-46 PMID: 16909889 |

Baker SP, Grant PA, The proteasome: not just degrading anymore., 2005; Cell. 123(3) 361-3 PMID: 16269325 |

Daniel JA, Pray-Grant MG, Grant PA, Effector proteins for methylated histones: an expanding family., 2005; Cell cycle (Georgetown, Tex.). 4(7) 919-26 PMID: 15970672 |

Pray-Grant MG, Daniel JA, Schieltz D, Yates JR, Grant PA, Chd1 chromodomain links histone H3 methylation with SAGA- and SLIK-dependent acetylation., 2005; Nature. 433(7024) 434-8 PMID: 15647753 |

McMahon SJ, Pray-Grant MG, Schieltz D, Yates JR, Grant PA, Polyglutamine-expanded spinocerebellar ataxia-7 protein disrupts normal SAGA and SLIK histone acetyltransferase activity., 2005; Proceedings of the National Academy of Sciences of the United States of America. 102(24) 8478-82 PMID: 15932941 | PMCID: PMC1150861