Structural mechanism of HP1⍺-dependent transcriptional repression and chromatin compaction.

Heterochromatin protein 1 (HP1) plays a central role in establishing and maintaining constitutive heterochromatin. However, the mechanisms underlying HP1-nucleosome interactions and their contributions to heterochromatin functions remain elusive. Here, we present the cryoelectron microscopy (cryo-EM) structure of an HP1α dimer bound to an H2A.Z-nucleosome, revealing two distinct HP1α-nucleosome interfaces. The primary HP1α binding site is located at the N terminus of histone H3, specifically at the trimethylated lysine 9 (K9me3) region, while a secondary binding site is situated near histone H2B, close to nucleosome superhelical location 4 (SHL4). Our biochemical data further demonstrates that HP1α binding influences the dynamics of DNA on the nucleosome. It promotes DNA unwrapping near the nucleosome entry and exit sites while concurrently restricting DNA accessibility in the vicinity of SHL4. Our study offers a model for HP1α-mediated heterochromatin maintenance and gene silencing. It also sheds light on the H3K9me-independent role of HP1 in responding to DNA damage. [Display omitted] • The cryo-EM structure of a human HP1α dimer bound to an H2A.Z nucleosome was determined • H3K9me-independent binding of HP1α is mediated by chromodomain-H2B interactions • HP1α promotes DNA unwrapping near the nucleosome entry/exit site The HP1 protein plays a crucial role in maintaining and spreading heterochromatin. Sokolova et al. employed an integrative structural biology approach to determine the structure of human HP1 α in complex with an H2A.Z nucleosome. [ABSTRACT FROM AUTHOR]