H2A.Z deposition by the SWR complex is stimulated by polyadenine DNA sequences in nucleosomes

The variant histone H2A.Z is deposited into nucleosomes immediately downstream of promoters, where it plays a critical role in transcription. The site-specific deposition of H2A.Z is catalyzed by the SWR complex, a conserved chromatin remodeler with affinity for promoter-proximal nucleosome-depleted regions (NDRs) and histone acetylation. By comparing the genomic distribution of H2A.Z in wild-type and SWR-deficient cells, we found that SWR is also responsible for depositing H2A.Z at thousands of non-canonical sites not directly linked to NDRs or histone acetylation. To understand the targeting mechanism of H2A.Z, we presented SWR to a library of canonical nucleosomes isolated from yeast and analyzed the preferred substrates. Our results revealed that SWR preferentially deposited H2A.Z into a subset of endogenous H2A.Z sites, which are overrepresented by polyadenine tracts on the top strands of the DNA duplex at the nucleosomal entry-exit sites. Insertion of polyadenine sequences into recombinant nucleosomes near the outgoing H2A-H2B dimer enhanced SWR’s affinity for the nucleosomal substrate and increased its H2A.Z insertion activity. These findings suggest that the genome encodes sequence-based information that facilitates remodeler-mediated targeting of H2A.Z.