School of Fundamental Sciences, Massey University, Private Bag 11-222, Palmerston North 4442, New Zealand.
Instituto de Química Física 'Rocasolano', CSIC, Serrano 119, 28006 Madrid, Spain.
Nucleic Acids Res. 2020 Jan 24;48(2):682-693. doi: 10.1093/nar/gkz1138.
The eukaryotic genome is functionally organized into domains of transcriptionally active euchromatin and domains of highly compact transcriptionally silent heterochromatin. Heterochromatin is constitutively assembled at repetitive elements that include the telomeres and centromeres. The histone code model proposes that HP1α forms and maintains these domains of heterochromatin through the interaction of its chromodomain with trimethylated lysine 9 of histone 3, although this interaction is not the sole determinant. We show here that the unstructured hinge domain, necessary for the targeting of HP1α to constitutive heterochromatin, recognizes parallel G-quadruplex (G4) assemblies formed by the TElomeric Repeat-containing RNA (TERRA) transcribed from the telomere. This provides a mechanism by which TERRA can lead to the enrichment of HP1α at telomeres to maintain heterochromatin. Furthermore, we show that HP1α binds with a faster association rate to DNA G4s of parallel topology compared to antiparallel G4s that bind slowly or not at all. Such G4-DNAs are found in the regulatory regions of several oncogenes. This implicates specific non-canonical nucleic acid structures as determinants of HP1α function and thus RNA and DNA G4s need to be considered as contributors to chromatin domain organization and the epigenome.
真核基因组在功能上组织成转录活跃的常染色质域和高度紧凑的转录沉默异染色质域。异染色质是由包括端粒和着丝粒在内的重复元件组成的。组蛋白密码模型提出，HP1α 通过其 chromodomain 与组蛋白 3 上的三甲基化赖氨酸 9 相互作用形成并维持这些异染色质域，尽管这种相互作用不是唯一的决定因素。我们在这里表明，对于 HP1α 靶向组成性异染色质所必需的无结构铰链域，可识别由端粒转录的端粒重复 RNA (TERRA) 形成的平行 G-四链体 (G4) 组装。这为 TERRA 可以导致 HP1α 在端粒处富集以维持异染色质提供了一种机制。此外，我们还表明，与结合缓慢或根本不结合的反平行 G4 相比，HP1α 以更快的结合速率与平行拓扑的 DNA G4 结合。这种 G4-DNA 存在于几个癌基因的调控区域。这暗示特定的非 canonical 核酸结构是 HP1α 功能的决定因素，因此 RNA 和 DNA G4 需要被认为是染色质结构域组织和表观基因组的贡献者。
