Researchers from Yale University led by Professor Antonio Giraldez have recently discovered that two proteins, P300 and Brd4, are both required and sufficient to enable the activation of genetic self-regulation in zebrafish embryos. Understanding how this genetic activation is controlled is crucial for a deeper understanding of the fundamentals of animal development. The research was published in Developmental Cell.
A newly-fertilized egg must activate its own genetic program in order to become independent from maternally-provided proteins in the egg: a process called transcriptional activation. This is the fundamental “first step” of embryogenesis without which further development could not take place. Now, Giraldez’s team has uncovered a role for two proteins, P300 and Brd4, in increasing transcriptional activation during embryonic development.
“Activation is a cornerstone of embryo development across all animals, it marks the beginning of life from a molecular standpoint” says graduate student Henry Chan. “We report that activation begins at the miR-430 locus in a stochastic manner. We further demonstrate that the timing of activation is regulated via the function of P300 and Brd4”.
Previous research has shown that histones, proteins that package and store DNA, have a repressive effect on transcription. In contrast, histone acetylation, the process by which molecules called acetyl groups are attached to histones, results in looser packing of DNA by histones, allowing increased transcription. P300 and Brd4 proteins are associated with histone acetylation, so the researchers injected them at early stages to see if they could increase transcription artificially. It worked, and the reverse was also true: blocking P300 and Brd4 blocked transcription, which blocked normal development. The results show that P300 and Brd4 are both required and sufficient for transcriptional activation in the developing vertebrate embryo.
“It was a tremendously exciting moment, when we saw that injecting those proteins into the embryo could prematurely fire up the genome,” Giraldez says. He continues, adding “It provides a new key to unlocking this important step in the beginning of a new life”.
The new research addresses a long-standing debate in the field over how transcriptional activation is controlled during development. Previous studies have explored the role of the cell cycle, which could theoretically titrate out the proteins necessary for activation. But Giraldez and his team showed that stopping the cell cycle during early embryonic development did not affect time-dependent genome activation, suggesting the length of the cell cycle is not a major factor in transcriptional activation. Instead, P300 and Brd4 appear to play a more important role in genome activation. The discovery of the key roles of P300 and Brd4 will pave the way for future research in developmental genetics.