Preserving the spatial positions of individual cells within tissues while obtaining single-cell-resolution DNA methylation profiles has been a significant technical challenge.  

Now, a research group led by Prof. LIU Jiang from the Institute of Biophysics of the Chinese Academy of Sciences has developed a new technology called SmC-seq that overcomes this limitation. SmC-seq enables spatially resolved, whole-genome DNA methylation analysis directly on tissue sections.

Their results were published in Nature Methods on April 27.

Using SmC-seq, the researchers generated a spatiotemporal atlas of DNA methylation during mammalian post-implantation embryonic development.

This new method combines a microfluidic chip system with enzymatic 5mC conversion technology. By removing histones in situ, the researchers effectively minimized the interference of chromatin structure with enzymatic reactions, thereby achieving uniform genome-wide sequencing coverage.

SmC-seq achieves in situ whole-genome methylation profiling at true single-cell resolution of 10 μm directly on tissue sections. In terms of throughput, a single experiment can capture approximately 10,000 cells.

Importantly, while preserving the native spatial information of cells, SmC-seq delivers data quality comparable to that of current single-cell DNA methylation technologies that lack spatial resolution.

A major outstanding question in developmental biology is how mammalian embryos and maternal uterine tissues interact following implantation. To address this question, the researchers applied SmC-seq to investigate this critical developmental period.

Unexpectedly, they discovered that maternal decidual cells undergo genome-wide DNA demethylation after embryo implantation. These cells then differentiate into a specialized population that likely provides nutritional support for yolk sac formation during mammalian embryogenesis. 

These findings provide the first direct evidence of how the mammalian yolk sac originates and becomes established during development.

Beyond embryology, the researchers noted that SmC-seq could serve as a versatile platform for spatial epigenomic mapping in studies of development, aging, and human disease.