Chromatin plays a pivotal role in all DNA-based processes within eukaryotes. It exists in two distinct forms: the transcriptionally active euchromatin and the transcriptionally repressive heterochromatin. Constitutive Heterochromatin, characterized by regions in the genome that remain condensed throughout the cell cycle, holds paramount significance for maintaining genome stability. It stands out due to its abundance of DNA tandem repeats and the prevalence of histone H3 methylation at Lysine 9 (H3K9me). Another key feature of constitutive heterochromatin is the enrichment of the nuclear protein heterochromatin protein 1 (HP1), which plays a central role in both establishing and maintaining heterochromatin. However, the precise mechanism governing how interactions between HP1 and nucleosomes contribute to its heterochromatin functions remains an enigma.
To unravel the mechanism of action of this crucial epigenetic regulator, we have adopted a multidisciplinary approach to dissect the intricate interplay between human HP1𝒶 and the nucleosome. Our efforts have yielded the cryo-EM structure of a human HP1α dimer in complex with the H2A.Z nucleosome. Leveraging MDFF (Molecular Dynamics Flexible Fitting) and cross-linking mass spectrometry techniques, we have constructed a structural model showing the extensive interactions of HP1α dimer with the nucleosome. Our structural insights, coupled with compelling biochemical data, elucidate that HP1α binding not only stabilizes DNA at an internal site but also concurrently enhances the unwrapping of terminal DNA segments on the nucleosome.
In sum, our study provides an important structural framework and offers mechanistic insights into chromatin compaction and gene silencing orchestrated by HP1.