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HP1α 依赖性转录抑制和染色质紧缩的结构机制。

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

机构信息

Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY, USA.

School of Molecular Sciences, Arizona State University, Tempe, AZ, USA.

出版信息

Structure. 2024 Nov 7;32(11):2094-2106.e6. doi: 10.1016/j.str.2024.09.013. Epub 2024 Oct 8.

DOI:10.1016/j.str.2024.09.013
PMID:39383876
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11560701/
Abstract

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.

摘要

异染色质蛋白 1（HP1）在建立和维持组成性异染色质方面发挥着核心作用。然而，HP1-核小体相互作用的机制及其对异染色质功能的贡献仍不清楚。在这里，我们展示了与 H2A.Z-核小体结合的 HP1α 二聚体的低温电子显微镜（cryo-EM）结构，揭示了两个截然不同的 HP1α-核小体界面。主要的 HP1α 结合位点位于组蛋白 H3 的 N 端，特别是在三甲基化赖氨酸 9（K9me3）区域，而次要的结合位点位于组蛋白 H2B 附近，靠近核小体超螺旋位置 4（SHL4）。我们的生化数据进一步表明，HP1α 结合影响核小体上 DNA 的动力学。它促进核小体进入和退出位点附近的 DNA 解旋，同时限制 SHL4 附近的 DNA 可及性。我们的研究为 HP1α 介导的异染色质维持和基因沉默提供了模型。它还揭示了 HP1 在应对 DNA 损伤时 H3K9me 独立的作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6c9d/11560701/cbff864c1484/nihms-2025446-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6c9d/11560701/6ad74b114894/nihms-2025446-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6c9d/11560701/8c8396014e9e/nihms-2025446-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6c9d/11560701/580a4e44fd4f/nihms-2025446-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6c9d/11560701/31585eb9f36f/nihms-2025446-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6c9d/11560701/b0c09b1a4b68/nihms-2025446-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6c9d/11560701/cbff864c1484/nihms-2025446-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6c9d/11560701/6ad74b114894/nihms-2025446-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6c9d/11560701/8c8396014e9e/nihms-2025446-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6c9d/11560701/580a4e44fd4f/nihms-2025446-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6c9d/11560701/31585eb9f36f/nihms-2025446-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6c9d/11560701/b0c09b1a4b68/nihms-2025446-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6c9d/11560701/cbff864c1484/nihms-2025446-f0006.jpg

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