Nuclear Localization of Mitochondrial TCA Cycle Enzymes as a Critical Step in Mammalian Zygotic Genome Activation

Raghavendra Nagaraj; Mark S Sharpley; Fangtao Chi; Daniel Braas; Yonggang Zhou; Rachel Kim; Amander T Clark; Utpal Banerjee

doi:10.1016/j.cell.2016.12.026

Nuclear Localization of Mitochondrial TCA Cycle Enzymes as a Critical Step in Mammalian Zygotic Genome Activation

Cell. 2017 Jan 12;168(1-2):210-223.e11. doi: 10.1016/j.cell.2016.12.026. Epub 2017 Jan 12.

Authors

Raghavendra Nagaraj¹, Mark S Sharpley¹, Fangtao Chi¹, Daniel Braas², Yonggang Zhou¹, Rachel Kim¹, Amander T Clark³, Utpal Banerjee⁴

Affiliations

¹ Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
² UCLA Center for Metabolomics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
³ 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.
⁴ 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.

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.

MeSH terms

Animals
Blastocyst / metabolism
Cell Nucleus / metabolism
Citric Acid Cycle*
Epigenesis, Genetic
Genome*
Glycosylation
Histones / metabolism
Ketone Oxidoreductases / metabolism
Mice
Mitochondria / enzymology
Mitochondria / metabolism
Pyruvic Acid / metabolism
Zygote / metabolism*

Substances

Histones
Pyruvic Acid
Ketone Oxidoreductases

Grants and funding

DP1 DK098059/DK/NIDDK NIH HHS/United States