Maintenance of nucleosomal balance in cis by conserved AAA-ATPase Yta7.

Abstract

The extent of chromatin compaction is a fundamental driver of nuclear metabolism . Yta7 is a chromatin-associated AAA-ATPase, the human ortholog of which, ANCCA/ATAD2 transcriptionally activates pathways of malignancy in a broad range of cancers. Yta7 directly binds histone H3, and bulk chromatin exhibits increased nucleosomal density in yta7Δ mutants. The suppression of yta7Δ mutant growth and transcriptional phenotypes in budding yeast by decreased dosage of histones H3 and H4 indicates the acute sensitivity of cells to deviations in nucleosome spacing. This study investigated the global changes in chromatin structure upon Yta7 loss or overexpression and determined which of these effects reflected direct Yta7 activity. Metagene analysis of Yta7's genome-wide localization indicated peak binding of Yta7 just downstream of the transcription start site. Cells lacking Yta7 exhibited increased nucleosome density within genes downstream of the +1 nucleosome, as defined by decreased internucleosomal distance, resulting in progressively 5'-shifted nucleosomes within the gene. In contrast, cells overexpressing Yta7 displayed profound 3'-shifts in nucleosome position and reduced nucleosome density within genes. Importantly, Yta7-bound regions were enriched for nucleosomal shifts, indicating that Yta7 acted locally to modulate nucleosome spacing. The phenotype of cells lacking both Yta7 and Rtt106, the histone H3/H4 chaperone, indicated that Yta7 functions in both Rtt106-dependent and Rtt106-independent ways to modulate nucleosome spacing within genes. This study suggested that Yta7 affected nucleosome density throughout the gene by both blocking Rtt106 from entering the gene, as shown previously at HTA1, and facilitating the loss of nucleosomes from the 5'-end.