Strand-specific single-cell methylomics reveals distinct modes of DNA demethylation dynamics during early mammalian development

Maya Sen, Dylan Mooijman, Alex Chialastri, Jean-Charles Boisset, Mina Popovic, Björn Heindryckx, Susana M. Chuva de Sousa Lopes, Siddharth S. Dey () and Alexander Oudenaarden ()
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Maya Sen: Hubrecht Institute-KNAW (Royal Netherlands Academy of Arts and Sciences) and University Medical Center Utrecht
Dylan Mooijman: Hubrecht Institute-KNAW (Royal Netherlands Academy of Arts and Sciences) and University Medical Center Utrecht
Alex Chialastri: University of California Santa Barbara
Jean-Charles Boisset: Hubrecht Institute-KNAW (Royal Netherlands Academy of Arts and Sciences) and University Medical Center Utrecht
Mina Popovic: Ghent University Hospital
Björn Heindryckx: Ghent University Hospital
Susana M. Chuva de Sousa Lopes: Ghent University Hospital
Siddharth S. Dey: University of California Santa Barbara
Alexander Oudenaarden: Hubrecht Institute-KNAW (Royal Netherlands Academy of Arts and Sciences) and University Medical Center Utrecht

Nature Communications, 2021, vol. 12, issue 1, 1-10

Abstract: Abstract DNA methylation (5mC) is central to cellular identity. The global erasure of 5mC from the parental genomes during preimplantation mammalian development is critical to reset the methylome of gametes to the cells in the blastocyst. While active and passive modes of demethylation have both been suggested to play a role in this process, the relative contribution of these two mechanisms to 5mC erasure remains unclear. Here, we report a single-cell method (scMspJI-seq) that enables strand-specific quantification of 5mC, allowing us to systematically probe the dynamics of global demethylation. When applied to mouse embryonic stem cells, we identified substantial cell-to-cell strand-specific 5mC heterogeneity, with a small group of cells displaying asymmetric levels of 5mCpG between the two DNA strands of a chromosome suggesting loss of maintenance methylation. Next, in preimplantation mouse embryos, we discovered that methylation maintenance is active till the 16-cell stage followed by passive demethylation in a fraction of cells within the early blastocyst at the 32-cell stage of development. Finally, human preimplantation embryos qualitatively show temporally delayed yet similar demethylation dynamics as mouse embryos. Collectively, these results demonstrate that scMspJI-seq is a sensitive and cost-effective method to map the strand-specific genome-wide patterns of 5mC in single cells.

Date: 2021
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DOI: 10.1038/s41467-021-21532-6

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