title: Inhibition of histone deacetylation promotes abnormal epidermal differentiation and specifically suppresses the expression of the late differentiation marker profilaggrin.
abstract: Reversible protein acetylation modulates higher-order chromatin structure and transcription activity of the genome. The reversible acetylation is executed by the intrinsic acetylase and deacetylase activities of co-regulators associated with the regulatory regions. Compounds capable of inhibiting deacetylase activity are a powerful tool for dissecting the role of protein acetylation in gene function. The ability of the deacetylase inhibitors to preferentially affect the homeostasis of transformed cells has also prompted studies for their clinical application. We present evidence that deacetylase inhibition with trichostatin A (TSA) affects the normal epidermal tissue architecture and pattern of expression by a mechanism(s) that does not correlate directly with the hyperacetylated histone status. While promoting abnormal differentiation, TSA specifically represses transcription initiation of the differentiation marker profilaggrin. Multiple factors, among which we have identified decreased Sp1 binding, a local decrease in acetylation activity, and enhanced synthesis and recruitment of a repressor histone demethylase, alter the chromatin configuration over the promoter, ultimately blocking its activation by c-jun. As compromised profilaggrin production leads to epidermal and consequently allergic disorders, our findings emphasize the need for a detailed investigation of the role deacetylase inhibitors may play in the maintenance of epidermal homeostasis in order to optimize their clinical applicability.
authors.affiliation: Department of Oral Biology and Pathology, The Living Skin Bank, School of Dental Medicine, SUNY Stony Brook, Stony Brook, New York 11794-8702, USA. nmarkova@notes.cc.sunysb.edu
authors.forename: Nelli G
authors.initials: NG
authors.lastname: Markova
authors.forename: Nevena
authors.initials: N
authors.lastname: Karaman-Jurukovska
authors.forename: Adriana
authors.initials: A
authors.lastname: Pinkas-Sarafova
authors.forename: Liuben N
authors.initials: LN
authors.lastname: Marekov
authors.forename: Marcia
authors.initials: M
authors.lastname: Simon
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000078404:Epidermal Cells; D004817:Epidermis / Q000502:physiology*; D000091344:Filaggrin Proteins; D005786:Gene Expression Regulation / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000502:physiology; D056466:Histone Demethylases; D006657:Histones / Q000378:metabolism*; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007381:Intermediate Filament Proteins / Q000235:genetics / Q000378:metabolism*; D015603:Keratinocytes / Q000166:cytology / Q000502:physiology*; D008297:Male; D010089:Oxidoreductases, N-Demethylating / Q000502:physiology; D011494:Protein Kinases / Q000502:physiology; D016755:Proto-Oncogene Proteins c-jun / Q000502:physiology
chemical_list: D004791:Enzyme Inhibitors; D000091344:Filaggrin Proteins; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D007381:Intermediate Filament Proteins; D016755:Proto-Oncogene Proteins c-jun; C012589:trichostatin A; D056466:Histone Demethylases; C495195:KDM1A protein, human; D010089:Oxidoreductases, N-Demethylating; D011494:Protein Kinases; C065999:Sp1 kinase; D006655:Histone Deacetylases