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三维染色质区分 dMes-4/NSD 和 Hypb/dSet2，以保护基因免受 H3K27me3 沉默。

Chromatin in 3D distinguishes dMes-4/NSD and Hypb/dSet2 in protecting genes from H3K27me3 silencing.

机构信息

Chromatin Dynamics and Cell Proliferation, Center of Integrative Biology, Molecular, Cellular and Developmental Biology (MCD/UMR5087), CNRS, Université Paul Sabatier de Toulouse, Toulouse, France.

Institut Curie, Paris Sciences et Lettres Research University; INSERM U934/ CNRS UMR3215, Paris, France.

出版信息

Life Sci Alliance. 2023 Sep 8;6(11). doi: 10.26508/lsa.202302038. Print 2023 Nov.

DOI:10.26508/lsa.202302038
PMID:37684044
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10491495/
Abstract

Cell type-specific barcoding of genomes requires the establishment of hundreds of heterochromatin domains where heterochromatin-associated repressive complexes hinder chromatin accessibility thereby silencing genes. At heterochromatin-euchromatin borders, regulation of accessibility not only depends on the delimitation of heterochromatin but may also involve interplays with nearby genes and their transcriptional activity, or alternatively on histone modifiers, chromatin barrier insulators, and more global demarcation of chromosomes into 3D compartmentalized domains and topological-associating domain (TADs). Here, we show that depletion of H3K36 di- or tri-methyl histone methyltransferases dMes-4/NSD or Hypb/dSet2 induces reproducible increasing levels of H3K27me3 at heterochromatin borders including in nearby promoters, thereby repressing hundreds of genes. Furthermore, dMes-4/NSD influences genes demarcated by insulators and TAD borders, within chromatin hubs, unlike transcription-coupled action of Hypb/dSet2 that protects genes independently of TADs. Insulator mutants recapitulate the increase of H3K27me3 upon dMes-4/NSD depletion unlike Hypb/dSet2. Hi-C data demonstrate how dMes-4/NSD blocks propagation of long-range interactions onto active regions. Our data highlight distinct mechanisms protecting genes from H3K27me3 silencing, highlighting a direct influence of H3K36me on repressive TADs.

摘要

基因组的细胞类型特异性条形码化需要建立数百个异染色质域，其中异染色质相关的抑制性复合物阻碍染色质可及性，从而沉默基因。在异染色质-常染色质边界，可及性的调节不仅取决于异染色质的限定，还可能涉及与附近基因及其转录活性的相互作用，或者依赖于组蛋白修饰酶、染色质屏障绝缘子和更全局的染色体划分为 3D 分区域和拓扑关联域 (TAD)。在这里，我们表明 H3K36 二甲基或三甲基组蛋白甲基转移酶 dMes-4/NSD 或 Hypb/dSet2 的耗竭会在异染色质边界（包括附近的启动子）处诱导可重复的 H3K27me3 水平升高，从而抑制数百个基因。此外，dMes-4/NSD 影响由绝缘子和 TAD 边界标记的基因，而不像 Hypb/dSet2 的转录偶联作用那样独立于 TAD 保护基因。与 Hypb/dSet2 不同，绝缘子突变体在 dMes-4/NSD 耗竭时会重现 H3K27me3 的增加。Hi-C 数据表明 dMes-4/NSD 如何阻止长距离相互作用传播到活跃区域。我们的数据突出了保护基因免受 H3K27me3 沉默的不同机制，强调了 H3K36me 对抑制性 TAD 的直接影响。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4cd9/10491495/d9847686ae23/LSA-2023-02038_FigS6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4cd9/10491495/5dfffb36729f/LSA-2023-02038_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4cd9/10491495/fabd9d1301cf/LSA-2023-02038_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4cd9/10491495/0f3edc2e61a1/LSA-2023-02038_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4cd9/10491495/c60a70a97c8b/LSA-2023-02038_FigS2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4cd9/10491495/979b68946f8d/LSA-2023-02038_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4cd9/10491495/63dc3d6776f9/LSA-2023-02038_FigS3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4cd9/10491495/de8cb7f6c5a7/LSA-2023-02038_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4cd9/10491495/525d7719d7ce/LSA-2023-02038_FigS4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4cd9/10491495/4d196a693769/LSA-2023-02038_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4cd9/10491495/7acbfebaa2c6/LSA-2023-02038_FigS5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4cd9/10491495/ad5db160c0a7/LSA-2023-02038_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4cd9/10491495/d9847686ae23/LSA-2023-02038_FigS6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4cd9/10491495/5dfffb36729f/LSA-2023-02038_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4cd9/10491495/fabd9d1301cf/LSA-2023-02038_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4cd9/10491495/0f3edc2e61a1/LSA-2023-02038_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4cd9/10491495/c60a70a97c8b/LSA-2023-02038_FigS2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4cd9/10491495/979b68946f8d/LSA-2023-02038_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4cd9/10491495/63dc3d6776f9/LSA-2023-02038_FigS3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4cd9/10491495/de8cb7f6c5a7/LSA-2023-02038_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4cd9/10491495/525d7719d7ce/LSA-2023-02038_FigS4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4cd9/10491495/4d196a693769/LSA-2023-02038_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4cd9/10491495/7acbfebaa2c6/LSA-2023-02038_FigS5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4cd9/10491495/ad5db160c0a7/LSA-2023-02038_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4cd9/10491495/d9847686ae23/LSA-2023-02038_FigS6.jpg

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