title: Changing the selectivity of p300 by acetyl-CoA modulation of histone acetylation.
abstract: Determining how histone acetylation is regulated is vital for treating the many diseases associated with its misregulation, including heart disease, neurological disorders, and cancer. We have previously reported that acetyl-CoA levels alter p300 histone acetylation in a site-specific manner in vitro. Here, we further investigate how changing acetyl-CoA concentrations alter the histone acetylation pattern by altering p300 specificity. Interestingly, these changes are not a simple global change in acetylation, but rather site specific changes, whereby acetylation at some sites increase while others decrease. We also demonstrate how the p300 inhibitor C646 can pharmacologically alter p300 histone acetylation patterns in vitro and in cells. This study provides insight into the mechanisms regulating p300 residue specificity, a potential means for altering p300 dependent histone acetylation, and an investigation into altering histone acetylation patterns in cells.
authors.affiliation: Department of Cancer Biology, 333 Cottman Avenue, Fox Chase Cancer Center , Philadelphia, Pennsylvania United States.
authors.forename: Ryan A
authors.initials: RA
authors.lastname: Henry
authors.forename: Yin-Ming
authors.initials: YM
authors.lastname: Kuo
authors.forename: Vikram
authors.initials: V
authors.lastname: Bhattacharjee
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Yen
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Andrews
mesh_terms: D000105:Acetyl Coenzyme A / Q000378:metabolism*; D000107:Acetylation / Q000187:drug effects; D001565:Benzoates / Q000494:pharmacology; D001665:Binding Sites; D050882:CREB-Binding Protein / Q000378:metabolism*; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D016895:Culture Media, Serum-Free; D004305:Dose-Response Relationship, Drug; D050881:E1A-Associated p300 Protein / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006657:Histones / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D009578:Nitrobenzenes; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011720:Pyrazoles / Q000494:pharmacology; D047069:Pyrazolones; D053719:Tandem Mass Spectrometry / Q000379:methods
chemical_list: C584509:4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid; D001565:Benzoates; D016895:Culture Media, Serum-Free; D006657:Histones; D009578:Nitrobenzenes; D011720:Pyrazoles; D047069:Pyrazolones; D000105:Acetyl Coenzyme A; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human