title: Substantial histone reduction modulates genomewide nucleosomal occupancy and global transcriptional output.
abstract: The basic unit of genome packaging is the nucleosome, and nucleosomes have long been proposed to restrict DNA accessibility both to damage and to transcription. Nucleosome number in cells was considered fixed, but recently aging yeast and mammalian cells were shown to contain fewer nucleosomes. We show here that mammalian cells lacking High Mobility Group Box 1 protein (HMGB1) contain a reduced amount of core, linker, and variant histones, and a correspondingly reduced number of nucleosomes, possibly because HMGB1 facilitates nucleosome assembly. Yeast nhp6 mutants lacking Nhp6a and -b proteins, which are related to HMGB1, also have a reduced amount of histones and fewer nucleosomes. Nucleosome limitation in both mammalian and yeast cells increases the sensitivity of DNA to damage, increases transcription globally, and affects the relative expression of about 10% of genes. In yeast nhp6 cells the loss of more than one nucleosome in four does not affect the location of nucleosomes and their spacing, but nucleosomal occupancy. The decrease in nucleosomal occupancy is non-uniform and can be modelled assuming that different nucleosomal sites compete for available histones. Sites with a high propensity to occupation are almost always packaged into nucleosomes both in wild type and nucleosome-depleted cells; nucleosomes on sites with low propensity to occupation are disproportionately lost in nucleosome-depleted cells. We suggest that variation in nucleosome number, by affecting nucleosomal occupancy both genomewide and gene-specifically, constitutes a novel layer of epigenetic regulation.
authors: San Raffaele University, Milan, Italy.
authors: Barbara
authors: B
authors: Celona
authors: Assaf
authors: A
authors: Weiner
authors: Francesca
authors: F
authors: Di Felice
authors: Francesco M
authors: FM
authors: Mancuso
authors: Elisa
authors: E
authors: Cesarini
authors: Riccardo L
authors: RL
authors: Rossi
authors: Lorna
authors: L
authors: Gregory
authors: Dilair
authors: D
authors: Baban
authors: Grazisa
authors: G
authors: Rossetti
authors: Paolo
authors: P
authors: Grianti
authors: Massimiliano
authors: M
authors: Pagani
authors: Tiziana
authors: T
authors: Bonaldi
authors: Jiannis
authors: J
authors: Ragoussis
authors: Nir
authors: N
authors: Friedman
authors: Giorgio
authors: G
authors: Camilloni
authors: Marco E
authors: ME
authors: Bianchi
authors: Alessandra
authors: A
authors: Agresti
mesh_terms: D000818:Animals; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D044127:Epigenesis, Genetic; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D016678:Genome; D024243:HMGB1 Protein / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008962:Models, Theoretical; D009707:Nucleosomes / Q000378:metabolism*; D012313:RNA / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D015003:Yeasts / Q000235:genetics / Q000378:metabolism
chemical_list: D024243:HMGB1 Protein; D006657:Histones; D009707:Nucleosomes; D012313:RNA; D004247:DNA