Nuclear Localization of Mitochondrial TCA Cycle Enzymes Is Critical to Genome Activation in Mammalian Zygotes

To turn on its genome — the full set of genes inherited from each parent — a mammalian embryo needs to relocate a group of proteins, researchers at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA have discovered. The metabolic proteins, normally found in the energy-generating mitochondria of cells, move to the DNA-containing nuclei about two days after a mouse embryo is fertilized, according to the new study, led by senior author Dr. Utpal Banerjee. The study was published in the January 12, 2017 issue of Cell and is titled “Nuclear Localization of Mitochondrial TCA Cycle Enzymes As a Critical Step in Mammalian Zygotic Genome Activation.” Early in development, a mammalian embryo — or zygote — has all the materials it needs to grow and divide from genes and proteins that were contained in the egg cell. But after a few cell divisions, the zygote needs to activate its own genome. Researchers have never fully understood how this shift is made. They knew that certain metabolic compounds, such a pyruvate, were required, but had also observed that the mitochondria — which normally process pyruvate into energy — were small and inactive during this stage of development. Dr. Banerjee, a Professor of Molecular, Cell, and Developmental Biology and Co-Director of the UCLA Broad Stem Cell Research Center, and colleagues confirmed that pyruvate was required for zygotes to activate their genomes by growing mouse zygotes in a culture dish lacking pyruvate. Then, in both mouse and human embryos, researchers used a number of methods to determine the location of proteins that process pyruvate through a metabolic program called the tricarboxylic acid (TCA) cycle.
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