title: Histone deacetylase-dependent establishment and maintenance of broad low-level histone acetylation within a tissue-specific chromatin domain.
abstract: The murine beta-globin locus in adult erythroid cells is characterized by a broad pattern of erythroid-specific histone acetylation. The embryonic beta-globin genes Ey and betaH1 are located in a approximately 30 kb central subdomain characterized by low-level histone acetylation, while the fetal/adult genes betamajor and betaminor and the upstream locus control region reside in hyperacetylated chromatin. Histone deacetylase (HDAC) inhibitors induce H4 acetylation at the Ey promoter [Forsberg, E. C., Downs, K. M., Christensen, H. M., Im, H., Nuzzi, P. A., and Bresnick, E. H. (2000) Proc. Natl. Acad. Sci. U.S.A. 97, 14494-14499], indicating that HDACs maintain low-level H4 acetylation at this site. Since little is known about the establishment of broad histone modification patterns, we asked whether this mechanism applies only to the promoter or to the entire subdomain. We show that the HDAC inhibitor trichostatin A induces H4 hyperacetylation at multiple sites within the subdomain in erythroid cells. The hematopoietic factors p45/NF-E2, GATA-1, and erythroid kruppel-like factor (EKLF), which function through cis elements of the beta-globin locus, were not required for induction of H4 hyperacetylation. Analysis of chromatin structure within the subdomain revealed low accessibility to restriction endonucleases and nearly complete CpG dinucleotide methylation. Induction of H4 hyperacetylation did not restore hallmark features of transcriptionally active chromatin. We propose that an HDAC-dependent surveillance mechanism counteracts constitutive histone acetyltransferase (HAT) access, thereby maintaining low-level H4 acetylation throughout the subdomain.
authors.affiliation: Department of Pharmacology, Molecular and Cellular Pharmacology Program, University of Wisconsin Medical School, 383 Medical Science Center, 1300 University Avenue, Madison, Wisconsin 53706, USA.
authors.forename: Hogune
authors.initials: H
authors.lastname: Im
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Grass
authors.forename: Heather M
authors.initials: HM
authors.lastname: Christensen
authors.forename: Andrew
authors.initials: A
authors.lastname: Perkins
authors.forename: Emery H
authors.initials: EH
authors.lastname: Bresnick
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D016466:CHO Cells; D002843:Chromatin / Q000737:chemistry* / Q000378:metabolism*; D018899:CpG Islands; D006224:Cricetinae; D019175:DNA Methylation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004912:Erythrocytes / Q000378:metabolism; D005914:Globins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000737:chemistry* / Q000378:metabolism*; D006657:Histones / Q000737:chemistry / Q000378:metabolism*; D006877:Hydroxamic Acids / Q000494:pharmacology; D007939:Leukemia L1210; D019901:Locus Control Region; D051379:Mice; D009928:Organ Specificity / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000187:drug effects / Q000235:genetics; D015183:Restriction Mapping; D014407:Tumor Cells, Cultured
chemical_list: D002843:Chromatin; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; C012589:trichostatin A; D005914:Globins; D006655:Histone Deacetylases