Substantial histone reduction modulates genomewide nucleosomal occupancy and global transcriptional output

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.