Characterizing the single-cell DNA methylome of mouse and human preimplantation embryos

As these GEITP pages have often stated, a trait (phenotype) reflects the contribution of genetics (DNA sequence differences) plus epigenetics (chromosomal changes other than DNA sequence) plus adverse environmental insults that constantly affect DNA sequence and epigenetic variations. Epigenetics includes DNA-methylation, RNA-interference, histone modifications, and chromatin remodeling. These two papers [attached] describe DNA-methylation events that happen in pluripotent mouse, and human, pre-implantation embryos. In mammals, early lineage specification in pre-implantation and post-implantation embryonic development generates founder tissues for all subsequent somatic development.

The first lineage specification starts at the morula stage, when the inner cell mass (ICM) and the trophectoderm (TE) begin to segregate. The ICM contains both cells of the epiblast lineage, which give rise to the entire fetus, and cells of the primitive endoderm lineage, which form visceral endoderm and parietal endoderm. Visceral endoderm becomes the chief metabolic component of the visceral yolk sac, and parietal endoderm contributes to the transient parietal yolk sac. The TE contains progenitor cells for trophoblasts, which form the majority of the fetal-origin part of the placenta. In mice, by embryonic day 6.5 (E6.5), the anterior epiblast gives rise to ectoderm, and the posterior proximal epiblast develops into the primitive streak, which then forms mesoderm and endoderm. The resulting three germ layers contain virtually all progenitors for the future body plan (epiderm ––> skin; mesoderm ––> muscle and bone; and endoderm ––> internal organs such as liver).

However, the dynamics of transcriptomes (arising from DNA sequence ––> messenger RNA), and epigenomes (DNA-methylation, RNA-interference, histone modifications, and chromatin remodeling), acting in concert with initial cell fate commitment, remains poorly understood. Authors [first attached paper] report investigation of transcriptomes, and base-resolution methylomes, for early lineages in peri- and post-implantation mouse embryos. They found allele-specific and lineage-specific de novo DNA-methylation that leads to differential methylation between embryonic and extra-embryonic lineages at promoters of lineage regulators, gene bodies, and

DNA-methylation valleys. By defining chromatin architecture across the same developmental period –– authors demonstrated that both global demethylation and remethylation in early development correlate with chromatin compartments. Dynamic local methylation was evident during gastrulation, which enabled identification of putative regulatory elements. Lastly, authors found that de novo methylation patterning does not strictly require implantation. These findings thus reveal dynamic transcriptomes, DNA methylomes, and 3-dimensional chromatin landscapes during the earliest stages of mouse lineage specification.

Authors [second attached paper] performed single-cell DNA-methylome sequencing for human preimplantation embryos and found that tens of thousands of genomic loci exhibit de novo DNA-methylation. This observation indicates that genome-wide DNA-methylation reprogramming during pre-implantation development is in a dynamic balance between strong global demethylation and extremely-focused remethylation. Moreover, demethylation of the paternal genome is much faster and thorough than that of the maternal genome. From the two-cell zygote to the post-implantation stage, methylation of the paternal genome is consistently lower than that of the maternal genome. Authors also found that the genetic lineage of early blastomeres can be traced by DNA-methylation analysis. This breakthrough work paves the way for deciphering the secrets of DNA-methylation reprogramming in early human embryos.

Nat Genet Jan 2o18; 50: 12–19 & pp 96–105

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