One Gene to Start Them All

    No magical object is needed for zygotic genome activation (ZGA), the process that initiates gene transcription in newly fertilized oocytes, and thereby unleashes the genome’s latent powers. Instead, some of the earliest stages of embryonic development come down to an ordinary-seeming gene, one that has an unprepossessing name: DUX.

    The DUX gene attracted the piercing gaze of scientists based at École Polytechnique Fédérale de Lausanne (EPFL) while they were engaged in a seemingly irrelevant study. They noticed that in patients suffering from a form of muscular dystrophy, mutations led to the production in muscle cells of a protein called DUX4, which is normally detected only at the earliest stage of human embryonic development.

    They also found that when DUX4 is forcibly produced in muscle cells, it turns on a whole set of genes that are expressed during zygotic genome activation. After making this observation, the EPFL scientists decided to keep a close eye on DUX4. It could lead them, they reasoned, to one of the deepest secrets of the primordial cell, which is to say, the zygote.

    The zygote, which forms when the oocyte is fertilized by the sperm cell, carries one copy each of the maternal and paternal genomes. This genomic information, however, isn’t transcribed right away in animal embryos. It is only after ZGA that the first major wave of embryonic transcripts occurs.

    Although ZGA-triggering factors have been identified in fruit flies and zebrafish, analogous factors in mammals were still undefined when the EPFL team decided to turn its attention to DUX. Ultimately, the team conducted a study of the DUX family of proteins that ranged over varied terrain: transcription information from muscle cells (as noted earlier); publicly available data identifying which components of the human genome are expressed during the first few days of embryonic development; and observations from a gene knockout study that used mouse embryonic stem cells.

    This scientific trek was chronicled in an article that appeared May 1 in the journal Nature Genetics, in an article entitled, “DUX-Family Transcription Factors Regulate Zygotic Genome Activation in Placental Mammals.”

    “First, human DUX4 and mouse Dux are both expressed before ZGA in their respective species,” the article’s authors wrote. “Second, both orthologous proteins bind the promoters of ZGA-associated genes and activate their transcription. Third, Dux knockout in mouse embryonic stem cells (mESCs) prevents the cells from cycling through a 2-cell-like state. Finally, zygotic depletion of Dux leads to impaired early embryonic development and defective ZGA.”

    The authors emphasized that they obtained their final piece of evidence when they removed the DUX gene from fertilized mouse oocytes using CRISPR/Cas9 genome editing. This prevented zygotic genome activation altogether and precluded the growth of embryos beyond the first couple of cell divisions.

    The authors surmised that DUX4, and by extension the DUX family of proteins, is the master regulator responsible for kick-starting genome expression at the earliest stage of embryonic life in humans, mice, and probably all placental mammals.

    “An old enigma is solved,” said the EPFL’s Didier Trono, Ph.D. “The study sheds light on what triggers the genetic program that ultimately makes us what we are. It can also help us understand certain cases of infertility and perhaps guide the development of new treatments for DUX-related muscle dystrophies.”

    Dr. Trono and his team are now curious about what could unleash, in the first few hours of our embryonic life, the ephemeral yet so crucial production of this master regulator.