Expansion in situ genome sequencing links nuclear abnormalities to aberrant chromatin regulation

IF 45.8 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Pub Date : 2025-05-29 DOI:10.1126/science.adt2781

Ajay S. Labade, Zachary D. Chiang, Caroline Comenho, Paul L. Reginato, Andrew C. Payne, Andrew S. Earl, Rojesh Shrestha, Fabiana M. Duarte, Ehsan Habibi, Ruochi Zhang, George M. Church, Edward S. Boyden, Fei Chen, Jason D. Buenrostro

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Abstract

Microscopy and genomics are used to characterize cell function, but approaches to connect the two types of information are lacking, particularly at subnuclear resolution. Here, we describe expansion in situ genome sequencing (ExIGS), a technology that enables sequencing of genomic DNA and super-resolution localization of nuclear proteins in single cells. Applying ExIGS to progeria-derived fibroblasts revealed that lamin abnormalities are linked to hotspots of aberrant chromatin regulation that may erode cell identity. Lamin was found to generally repress transcription, suggesting that variation in nuclear morphology may affect gene regulation across tissues and aged cells. These results demonstrate that ExIGS may serve as a generalizable platform with which to link nuclear abnormalities to gene regulation, offering insights into disease mechanisms.

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扩增原位基因组测序将核异常与异常的染色质调节联系起来

显微镜和基因组学被用来描述细胞功能，但是缺乏将这两种信息联系起来的方法，特别是在亚核分辨率上。在这里，我们描述了扩展原位基因组测序（ExIGS），这是一种能够测序基因组DNA和超分辨率定位单细胞核蛋白的技术。将ExIGS应用于早衰性成纤维细胞表明，纤层蛋白异常与可能侵蚀细胞身份的异常染色质调节热点有关。研究发现，核纤层蛋白通常会抑制转录，这表明核形态的变化可能会影响组织和衰老细胞的基因调控。这些结果表明，ExIGS可以作为一个将核异常与基因调控联系起来的通用平台，为疾病机制提供见解。

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来源期刊

Science 综合性期刊-综合性期刊

CiteScore

61.10

自引率

0.90%

发文量

审稿时长

2.1 months

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