NIDDK intramural scientists studying mice have discovered that a protein capable of unleashing genes important to tissue formation has a second, independent job regulating early embryonic development. As a fertilized egg develops into an embryo, it must first grow and divide to organize into a ball of cells containing three distinct cellular layers, called germ layers. Each germ layer will go on to generate a specific subset of the organs, tissues, and cells that make up an organism. Embryonic stem (ES) cells grown in the laboratory can be coaxed to differentiate into the three germ layers, thus offering a model to understand factors influencing this critical aspect of early development. The UTX protein has already been shown to regulate processes important later in development, such as those governing generation of the heart and muscle cells. In some cases, this occurs when UTX exerts an enzymatic function that enables quiescent developmental genes to become activated. Now, researchers studying UTX in mouse ES cells and mouse embryos have discovered that this protein is also critical to an early step in development— formation of one of the three germ layers—and that this function is independent of its enzymatic activity.
Working in mouse ES cells, the researchers generated three experimental strains: a control strain with an intact UTX gene, a strain in which the UTX gene was deleted, and a strain in which the UTX gene was intact but mutated so that the protein produced no longer had enzymatic activity. These different strains were treated to encourage formation of germ layers. While apparently able to support formation of other germ layers, ES cells lacking UTX could not form a layer called the mesoderm. In contrast, ES cells with the mutated UTX developed similarly to the control cells—indicating that UTX, but not its enzymatic activity, was important to mesoderm formation. Further experiments revealed a possible mechanism: UTX protein binds to a DNA region controlling activation of the gene for Brachyury, a factor essential to mesoderm formation. In the absence of UTX, Brachyury gene activation in ES cells was reduced significantly, and could not be artificially induced—indicating that UTX is an essential component of the molecular machinery that activates Brachyury.
The UTX gene is found on the X chromosome and is thus normally present in both male and female mice. Male cells possess a gene on the Y chromosome, called UTY, that encodes a protein similar to UTX but which lacks detectable enzymatic activity. Suspecting that UTY may act like UTX, the researchers conducted a series of molecular experiments and found evidence suggesting that UTY can also activate Brachyury. To test whether UTX and UTY are important in actual embryonic development, the researchers mated mice to produce female embryos lacking UTX, and male embryos lacking UTX but retaining UTY. Female embryos lacking UTX had significantly reduced Brachyury activation, severe developmental defects similar to those seen in mouse embryos lacking the Brachyury gene, and died before birth. In contrast, male embryos lacking UTX, while suffering defects that made it impossible for them to survive much beyond birth, developed much more normally and activated Brachyury—further suggesting that UTX and UTY are functionally redundant early in development. Together, these findings shed further light on both early development and the multi-tasking of factors during development—information that could also be useful in recapitulating developmental processes important to regenerative medicine efforts.
Wang C, Lee J-E, Cho Y-W, et al. UTX regulates mesoderm differentiation of embryonic stem cells independent of H3K27 demethylase activity. Proc Natl Acad Sci USA 109: 15324-15329, 2012.