Regulation of gene expression at the beginning of mammalian development

The maternal to zygotic transition can be viewed as a cascade of events that begins when fertilization triggers the zygotic clock that delays early ZGA until formation of a 2-cell embryo. Early ZGA, in turn, appears to be required for expression of late ZGA, and late ZGA is required to form a 4- cell embryo. ZGA in mammals is a time-dependent mechanism rather than a cell cycle-dependent mechanism that delays both transcription and translation of nascent transcripts. Thus, zygotic gene transcripts appear to be handled differently than maternal mRNA, a phenomenon also observed in Xenopus (55). The length of this delay is species-dependent, occurring at the 2-cell stage in mice, the 4-8-cell stage in cows and humans, and the 8-16-cell stage in sheep and rabbits (4). However, concurrent with formation of a 2-cell embryo in the mouse and rabbit (47, 56), perhaps in all mammals, a general chromatin-mediated repression of promoter activity appears. Repression factors are inherited by the maternal pronucleus from the oocyte but are absent in the paternal pronucleus and not available until sometime during the transition from a late 1-cell to a 2-cell embryo. This means that paternally inherited genes are exposed to a different environment in fertilized eggs than are maternally inherited genes, a situation that could contribute to genomic imprinting. Chromatin-mediated repression of promoter activity prior to ZGA is similar to what is observed during Xenopus embryogenesis (31, 32) and ensures that genes are not expressed until the appropriate time in development when positive acting factors, such as enhancers, can relieve this repression. The ability to use enhancers appears to depend on the acquisition of specific co-activators at the 2-cell stage in mice and perhaps later in other mammals (47, 56), concurrent with ZGA. Even then, the mechanism by which enhancers communicate with promoters changes during development (Fig. 2), providing an opportunity for enhancer-mediated stimulation of TATA-less promoters (e.g. housekeeping genes) early during development while eliminating this mechanism later during development. The net result of this sequence of events is to impose a directionality at the very beginning of animal development. This directionality is evident from the inability of fertilized mouse eggs to reprogram gene expression in nuclei taken from cells at developmentally advanced stages. For example, nuclei transplanted from mouse embryos that have progressed beyond ZGA (>late 2-cell stage) into enucleated 1-cell embryos do not recapitulate the normal program of gene expression (45) and therefore do not support successful development (21, 39). At least two factors contribute to this phenomenon: the inability of 1-cell embryos to relieve repression once it has been established and their inability to utilize enhancers. Although S-phase-arrested 1-cell embryos can efficiently utilize promoters encoded in plasmid DNA, they cannot relieve repression of the same promoter if it is first injected into a 2-cell embryo and then the injected nucleus transplanted back into an arrested 1-cell embryo (35). Linking the promoter to the F101 enhancer does not stimulate activity under these conditions, presumably because enhancer-specific coactivator is absent in 1-cell embryos (Fig. 2). Thus, it is not surprising that the maternal pronucleus in 1-cell embryos can exist in a repressed state while the paternal pronucleus does not (33) (Fig. 1). The results described above have opened the door to understanding how the developmental program in mammals is initiated. It should now be possible to identify the roles of specific transcription factors and chromosomal changes in activating specific genes at the beginning of mammalian development.