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组织中DNA甲基化组和转录组的空间联合分析

Spatial joint profiling of DNA methylome and transcriptome in tissues.

作者信息

Lee Chin Nien, Fu Hongxiang, Cardilla Angelysia, Zhou Wanding, Deng Yanxiang

机构信息

Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Institute of RNA innovation, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

出版信息

Nature. 2025 Sep 3. doi: 10.1038/s41586-025-09478-x.


DOI:10.1038/s41586-025-09478-x
PMID:40903587
Abstract

The spatial resolution of omics analyses is fundamental to understanding tissue biology. The capacity to spatially profile DNA methylation, which is a canonical epigenetic mark extensively implicated in transcriptional regulation, is lacking. Here we introduce a method for whole-genome spatial co-profiling of DNA methylation and the transcriptome of the same tissue section at near single-cell resolution. Applying this technology to mouse embryogenesis and the postnatal mouse brain resulted in rich DNA-RNA bimodal tissue maps. These maps revealed the spatial context of known methylation biology and its interplay with gene expression. The concordance and distinction in spatial patterns of the two modalities highlighted a synergistic molecular definition of cell identity in spatial programming of mammalian development and brain function. By integrating spatial maps of mouse embryos at two different developmental stages, we reconstructed the dynamics that underlie mammalian embryogenesis for both the epigenome and transcriptome, revealing details of sequence-, cell-type- and region-specific methylation-mediated transcriptional regulation. This method extends the scope of spatial omics to include DNA cytosine methylation, enabling a more comprehensive understanding of tissue biology across development and disease.

摘要

组学分析的空间分辨率对于理解组织生物学至关重要。目前缺乏对DNA甲基化进行空间分析的能力,而DNA甲基化是一种广泛参与转录调控的典型表观遗传标记。在此,我们介绍一种方法,可在接近单细胞分辨率的水平上对同一组织切片的DNA甲基化和转录组进行全基因组空间共分析。将该技术应用于小鼠胚胎发育和出生后小鼠大脑,得到了丰富的DNA-RNA双峰组织图谱。这些图谱揭示了已知甲基化生物学的空间背景及其与基因表达的相互作用。两种模式在空间模式上的一致性和差异突出了在哺乳动物发育和脑功能的空间编程中细胞身份的协同分子定义。通过整合两个不同发育阶段小鼠胚胎的空间图谱,我们重建了表观基因组和转录组在哺乳动物胚胎发育过程中的动态变化,揭示了序列、细胞类型和区域特异性甲基化介导的转录调控细节。该方法将空间组学的范围扩展到包括DNA胞嘧啶甲基化,从而能够更全面地理解发育和疾病过程中的组织生物学。

相似文献

[1]
Spatial joint profiling of DNA methylome and transcriptome in tissues.

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[2]
Spatial joint profiling of DNA methylome and transcriptome in mammalian tissues.

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[3]
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本文引用的文献

[1]
Multiplexed spatial mapping of chromatin features, transcriptome and proteins in tissues.

Nat Methods. 2025-3

[2]
DNA methylation controls stemness of astrocytes in health and ischaemia.

Nature. 2024-10

[3]
Analyzing single-cell bisulfite sequencing data with MethSCAn.

Nat Methods. 2024-9

[4]
BISCUIT: an efficient, standards-compliant tool suite for simultaneous genetic and epigenetic inference in bulk and single-cell studies.

Nucleic Acids Res. 2024-4-12

[5]
A single-cell time-lapse of mouse prenatal development from gastrula to birth.

Nature. 2024-2

[6]
Essential transcription factors for induced neuron differentiation.

Nat Commun. 2023-12-15

[7]
Single-cell bisulfite-free 5mC and 5hmC sequencing with high sensitivity and scalability.

Proc Natl Acad Sci U S A. 2023-12-5

[8]
Single-cell DNA methylation and 3D genome architecture in the human brain.

Science. 2023-10-13

[9]
Joint single-cell profiling resolves 5mC and 5hmC and reveals their distinct gene regulatory effects.

Nat Biotechnol. 2024-6

[10]
Dictionary learning for integrative, multimodal and scalable single-cell analysis.

Nat Biotechnol. 2024-2

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