Genomic insights into chromatin reprogramming to totipotency in embryos

Abstract

The early embryo is the natural prototype for the acquisition of totipotency, which is the potential of a cell to produce a whole organism. Generation of a totipotent embryo involves chromatin reorganization and epigenetic reprogramming that alter DNA and histone modifications. Understanding embryonic chromatin architecture and how this is related to the epigenome and transcriptome will provide invaluable insights into cell fate decisions. Recently emerging low-input genomic assays allow the exploration of regulatory networks in the sparsely available mammalian embryo. Thus, the field of developmental biology is transitioning from microscopy to genome-wide chromatin descriptions. Ultimately, the prototype becomes a unique model for studying fundamental principles of development, epigenetic reprogramming, and cellular plasticity. In this review, we discuss chromatin reprogramming in the early mouse embryo, focusing on DNA methylation, chromatin accessibility, and higher-order chromatin structure.

Figure 1.

Overview of molecular events during mouse gametogenesis and preimplantation development. Male and female gametogenesis entail distinct timings of meiotic divisions (MI and MII) in relation to transcriptional activity and differentiation. The sperm genome is packaged around protamines that are rapidly exchanged to maternal histones at fertilization. Fertilization triggers resumption of oocyte meiosis (MII), and the totipotent zygote forms, containing two parental pronuclei. Totipotency declines with subsequent cleavage divisions. Maternal transcripts are rapidly degraded before ZGA, which occurs in two waves: minor ZGA in the late zygote and major ZGA in the two-cell embryo. DNA methylation dynamically changes in the zygote: paternal 5mC is lost, de novo paternal 5hmC forms, and passive dilution of DNA methylation occurs during cleavage divisions. Sp., spermatocyte.

Figure 2.

Proposed mechanisms of zygotic DNA demethylation. Passive DNA demethylation mechanisms include (i) replication-dependent passive dilution of 5mC or (ii) its Tet-catalyzed oxidation products (5hmC, 5fC, and 5caC) in the absence of maintenance DNA methylase DNMT1 or Tet hydroxylase, respectively. Active DNA demethylation mechanisms comprise (iii) active removal of 5mC via Tet3-catalyzed oxidation products involving activity of yet unidentified deaminase (*) and DNA glycosylases feeding into the BER pathway or (iv) direct removal of 5mC independent of Tet action involving an unknown deaminase (*) or demethylase. C, cytosine; T, thymidine; 5hmU, 5-hydroxymethyluracil.