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.

Toward a unified physical model of nucleosome patterns flanking transcription start sites

“…The active SNG model is compatible with the preserved nucleosome spacing at reduced histone abundance (13,15) and the seemingly contradictory finding that the normal in vivo nucleosome pattern is well described by the barrier nucleosome model without explicitly accounting for remodelers (7)(8)(9). The model predicts that a reduced histone abundance produces a slight downward slope in the average nucleosome pattern; i.e., the oscillatory density decays to the reduced average value at long distances from the reference nucleosome (SI Appendix, Fig.…”

“…Second, recent experiments have shown in vitro (13) and in vivo (14) that the formation of the native nucleosome pattern requires the action of remodeling enzymes. Moreover, reduction of the histone-DNA ratio in vitro (13) or in vivo (15) does not lead to a concomitant increase in the typical nucleosome spacing, as would be expected for statistical positioning. Do these observations invalidate the entire 1D gas framework or just the specific Kornberg-Stryer model?…”

Sterile inflammation and pregnancy complications: a review

“…HMGB1 is abundantly and ubiquitously expressed in nucleus where it plays a role in DNA replication, transcription and repair, and nucleosome stabilization (Boonyaratanakornkit et al 1998, Stros 2010, Celona et al 2011. HMGB1 is structured into two DNAbinding domains, HMG box A and B and an aspartic and glutamic acid-rich C-terminal tail.…”

Aspirin’s Active Metabolite Salicylic Acid Targets High Mobility Group Box 1 to Modulate Inflammatory Responses

“…Structurally, HMGB1 is composed of two basic DNA-binding domains, designated HMG boxes A and B, and a highly acidic C-terminal tail that participates in specific intramolecular interactions (14). In the nucleus, HMGB1 binds DNA to facilitate nucleosome formation and transcription factor binding (15). HMGB1 also acts as a DAMP molecule, with chemoattractant and cytokineinducing activities upon its release into the extracellular milieu from necrotic, damaged or severely stressed cells (16).…”