Zygote gene activation (ZGA): Starting the embryo’s own transcription for the first time in the fertilized egg

In mammals, after fertilization of the egg, what happens during the earliest minutes in the fertilized egg (zygote) has been a big black box before the 1990s. First it was found that maternal transcription in the fertilized oocyte is operational. But how does the early zygote depart from its seemingly blank state and transition itself into an embryonic transcriptionally active state? Factors that initiate this fascinating embryonic or zygotic genome activation (EGA or ZGA) process have been reported in animals such as the fly and zebrafish –– but little is known about the identity of “master regulators” of ZGA in mammals.

Three studies [attached] now add a missing piece of the ZGA puzzle –– suggesting that the family of double-homeodomain (DUX) transcription factors is instrumental in unleashing the first wave of transcription in the zygote of placental mammals. On page 925 of attached, authors report that mouse Dux and human DUX4 genes are expressed before the onset of ZGA and that they are activators of cleavage-stage genes and retroviral elements..!! Moreover, in some really cool experiments they show that DUX expression can convert mouse embryonic stem cells (mESCs) into two-cell-embryo-like (2C-like) cells in culture. On page 935 [attached], authors investigated func­tional evolution of the DUX family in mouse and human cells; their findings are also relevant for facioscapulohumeral dystrophy –– a congenital disorder caused by mis-expression of DUX4 in skeletal muscle. On page 941 [attached], authors show that DUX depletion in mESCs affects the formation of 2C-like cells, wheras in embryos it impairs early development. Altogether, these reports expand our knowledge about how the silence of the recently formed genome is broken and how new gene expression and chromatin patterns first emerge in the zygote.

One of the pillars of genetics, and indeed biomedical research, is the notion that heritable information required for cellular function is mainly encoded by DNA sequence. It is also widely documented that –– during the course of embryonic development and throughout adult­hood –– as cells replicate, differentiate and age, the genome becomes dynami­cally decorated with epigenetic marks (e.g. histone and DNA modifications) that correlate with different gene expression patterns, cell identity, and potency. The canonical perspective has been that this epigenetic information is then erased in the germ line and is thus not inherited by the next generation. This allows the newly formed zygote to start its development with an epigenomic “clean slate” to start with.

Nature Genetics June 2o17; 49: p 815 [1-page editorial]

Nature Genetics June 2o17; 49: 820–821 [News’N’Views) + pp 925–934 + 935–940 + 941–945 [three full articles]

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