title: Nuclear Localization of Mitochondrial TCA Cycle Enzymes as a Critical Step in Mammalian Zygotic Genome Activation.
abstract: Transcriptional control requires epigenetic changes directed by mitochondrial tricarboxylic acid (TCA) cycle metabolites. In the mouse embryo, global epigenetic changes occur during zygotic genome activation (ZGA) at the 2-cell stage. Pyruvate is essential for development beyond this stage, which is at odds with the low activity of mitochondria in this period. We now show that a number of enzymatically active mitochondrial enzymes associated with the TCA cycle are essential for epigenetic remodeling and are transiently and partially localized to the nucleus. Pyruvate is essential for this nuclear localization, and a failure of TCA cycle enzymes to enter the nucleus correlates with loss of specific histone modifications and a block in ZGA. At later stages, however, these enzymes are exclusively mitochondrial. In humans, the enzyme pyruvate dehydrogenase is transiently nuclear at the 4/8-cell stage coincident with timing of human embryonic genome activation, suggesting a conserved metabolic control mechanism underlying early pre-implantation development.
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Raghavendra
authors.initials: R
authors.lastname: Nagaraj
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Sharpley
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Fangtao
authors.initials: F
authors.lastname: Chi
authors.affiliation: UCLA Center for Metabolomics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Braas
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Yonggang
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Kim
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Amander T
authors.initials: AT
authors.lastname: Clark
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: banerjee@mbi.ucla.edu.
authors.forename: Utpal
authors.initials: U
authors.lastname: Banerjee
mesh_terms: D000818:Animals; D001755:Blastocyst / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D002952:Citric Acid Cycle; D044127:Epigenesis, Genetic; D016678:Genome; D006031:Glycosylation; D006657:Histones / Q000378:metabolism; D007658:Ketone Oxidoreductases / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism; D019289:Pyruvic Acid / Q000378:metabolism; D015053:Zygote / Q000378:metabolism*
chemical_list: D006657:Histones; D019289:Pyruvic Acid; D007658:Ketone Oxidoreductases