Proximity of H2A.Z containing nucleosome to the transcription start site influences gene expression levels in the mammalian liver and brain

Abstract

Nucleosome positioning maps of several organisms have shown that Transcription Start Sites (TSSs) are marked by nucleosome depleted regions flanked by strongly positioned nucleosomes. Using genome-wide nucleosome maps and histone variant occupancy in the mouse liver, we show that the majority of genes were associated with a single prominent H2A.Z containing nucleosome in their promoter region. We classified genes into clusters depending on the proximity of H2A.Z to the TSS. The genes with no detectable H2A.Z showed lowest expression level, whereas H2A.Z was positioned closer to the TSS of genes with higher expression levels. We confirmed this relation between the proximity of H2A.Z and expression level in the brain. The proximity of histone variant H2A.Z, but not H3.3 to the TSS, over seven consecutive nucleosomes, was correlated with expression. Further, a nucleosome was positioned over the TSS of silenced genes while it was displaced to expose the TSS in highly expressed genes. Our results suggest that gene expression levels in vivo are determined by accessibility of the TSS and proximity of H2A.Z.

Histone H2A.Z subunit exchange controls consolidation of recent and remote memory

“…2). Various studies have associated H2A.Z binding in the −1 nucleosome with steady-state gene activity 11,12 , but our data suggest that stimulus-induced changes in H2A.Z binding do not correlate with transcription at this time point.…”

“…However, consistent with the wide genomic distribution of H2A.Z 11 , our sequencing data demonstrate that its depletion both up- and downregulates 451 different genes, making it difficult to ascertain specific targets through which H2A.Z regulates memory.…”

“…H2A.Z positioning around the transcriptional start site (TSS) is strongly associated with transcription 11,14,15 . Using chromatin immunoprecipitation (ChIP), we investigated H2A.Z exchange at the −1 (first nucleosome upstream of the TSS) and +1 (first nucleosome downstream of the TSS) nucleosomes of memory-associated genes during consolidation (Fig.…”

“…H2A.Z has been associated with both positive and negative effects on transcription 11,12,22 , with acetylation having a positive effect 16,17,23 .Using acetylation as an indirect index of the transcriptional impact of H2A.Z, we found that 30 min after training, when H2A.Z exchange is most pronounced, acetylated H2A.Z (H2A.Zac) binding increased at the −1 nucleosome of Egr1 ( F 3,8 = 11.07, P = 0.03) and Fos ( F 3,8 = 3.92, P = 0.05). Consistent with H2A.Z eviction from the +1 nucleosome at 30 min, a subset of genes also exhibited reduced acetylation at the +1 nucleosome at this time point ( Egr2 : F 3,8 = 4.03, P = 0.05; Egr1 : F 3,8 = 14.13, P = 0.001) (Extended Data Fig.…”

Histone H3.3 regulates mitotic progression in mouse embryonic fibroblasts

“…Accordingly, genome-wide localization studies have mapped H2A.Z and H3.3 at promoter regions and TSS, and H3.3 density positively correlates with active transcription. However, H3.3 was also found to be associated with repressed genes and heterochromatic sites such as pericentric sites, telomeres, and retroviral elements (Drané et al 2010;Goldberg et al 2010;Bargaje et al 2012;Kraushaar et al 2013;Elsässer et al 2015). The difference in distribution may reflect distinct targeting chaperone complexes.…”