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H3K27me3 与基因组-核膜关联之间的拮抗作用驱动全能胚胎中非常规的空间基因组组织。

Antagonism between H3K27me3 and genome-lamina association drives atypical spatial genome organization in the totipotent embryo.

机构信息

Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht, Utrecht, the Netherlands.

Oncode Institute, Utrecht, the Netherlands.

出版信息

Nat Genet. 2024 Oct;56(10):2228-2237. doi: 10.1038/s41588-024-01902-8. Epub 2024 Sep 16.

DOI:10.1038/s41588-024-01902-8
PMID:39284976
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11525175/
Abstract

In mammals, early embryonic development exhibits highly unusual spatial positioning of genomic regions at the nuclear lamina, but the mechanisms underpinning this atypical genome organization remain elusive. Here, we generated single-cell profiles of lamina-associated domains (LADs) coupled with transcriptomics, which revealed a striking overlap between preimplantation-specific LAD dissociation and noncanonical broad domains of H3K27me3. Loss of H3K27me3 resulted in a restoration of canonical LAD profiles, suggesting an antagonistic relationship between lamina association and H3K27me3. Tethering of H3K27me3 to the nuclear periphery showed that the resultant relocalization is partially dependent on the underlying DNA sequence. Collectively, our results suggest that the atypical organization of LADs in early developmental stages is the result of a tug-of-war between intrinsic affinity for the nuclear lamina and H3K27me3, constrained by the available space at the nuclear periphery. This study provides detailed insight into the molecular mechanisms regulating nuclear organization during early mammalian development.

摘要

在哺乳动物中，早期胚胎发育表现出核纤层中基因组区域的高度异常空间定位，但支持这种非典型基因组组织的机制仍难以捉摸。在这里，我们生成了与转录组学相结合的核纤层相关结构域（LAD）的单细胞图谱，这揭示了植入前特异性 LAD 解离与 H3K27me3 的非典型广泛结构域之间的惊人重叠。H3K27me3 的缺失导致了规范 LAD 图谱的恢复，表明核纤层关联和 H3K27me3 之间存在拮抗关系。H3K27me3 与核周的束缚表明，由此产生的重定位部分依赖于潜在的 DNA 序列。总的来说，我们的结果表明，早期发育阶段 LAD 的非典型组织是核纤层固有亲和力与 H3K27me3 之间拔河的结果，受到核周可用空间的限制。这项研究为调节早期哺乳动物发育过程中核组织的分子机制提供了详细的见解。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a176/11525175/b1a5079eb3b3/41588_2024_1902_Fig12_ESM.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a176/11525175/058d7aa0c6f3/41588_2024_1902_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a176/11525175/cd2334fbcd5f/41588_2024_1902_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a176/11525175/e6f420184790/41588_2024_1902_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a176/11525175/43292a925963/41588_2024_1902_Fig6_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a176/11525175/322f4a3e7d10/41588_2024_1902_Fig7_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a176/11525175/54d37ecb8c61/41588_2024_1902_Fig8_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a176/11525175/8f0da3008a3b/41588_2024_1902_Fig9_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a176/11525175/85894ddc8433/41588_2024_1902_Fig10_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a176/11525175/8d6c2df9658c/41588_2024_1902_Fig11_ESM.jpg
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