Yap regulates anabolic glucose metabolism to support tissue growth   — ASN Events
  1. Schedule
  2. Session 8 (jointly with Cell-Dev Biology): Developmental Systems
  3. Yap regulates anabolic glucose metabolism to support tissue growth  

Yap regulates anabolic glucose metabolism to support tissue growth   (#31)

Andrew Cox 1 2 , Wolfram Goessling 3 4 5 6 7
  1. Peter MacCallum Cancer Centre, The University of Melbourne, Melbourne, Victoria, Australia
  2. Department of Biochemistry and Molecular Biology, The Univeristy of Melbourne, Melbourne, Victoria, Australia
  3. Harvard-MIT Division of Health Sciences and Technology, Boston, MA, USA
  4. Genetics Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
  5. Gastrointestinal Cancer Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
  6. Broad Institute of MIT and Harvard, Boston, MA, USA
  7. Harvard Stem Cell Institute, Boston, MA, USA

Aims

The Hippo pathway plays a central role in the regulation of organ size, stem cell homeostasis and cancer. Although many of the inputs into the Hippo pathway have been identified, less is known about how Yap target genes mediate the remarkable effects on tissue growth. The central aim of this study was to determine the impact of Yap on glucose metabolism. 

Methods

This study uses an innovative combination of transcriptomics (RNAseq), metabolomics (LC-MS/MS with 13C isotopic flux analysis) and imaging approaches (confocal microscopy) in vivo using transgenic and mutant zebrafish (Danio rerio). We complement these studies with ChIPseq analysis in cultured cancer cells and FDG-PET analysis in transgenic mice.

Results

Here, we show that yap-/- mutant zebrafish have defects in liver growth and hepatic progenitor potential that persist into adulthood. Transcriptional profiling reveals that Yap is necessary and sufficient to regulate expression of the glucose transporters, glut1 and glut2. Metabolic analysis identifies that yap-/- mutant zebrafish are glucose intolerant and exhibit decreased glycolytic flux into the anabolic biosynthesis of nucleotides. Further, normal glucose transport and nucleotide biosynthesis are conditionally required for Yap-driven liver growth. ChIPseq analysis in cultured human cancer cells reveals that Yap is enriched at an intragenic enhancer element in glut1. Finally, we demonstrate that the regulation of glut1 expression and glucose uptake by Yap is conserved in mice.

Conclusions

Taken together, our findings reveal that Yap directly induces glut1 via a conserved intragenic enhancer to facilitate glucose uptake and fuel the anabolic biosynthesis of nucleotides required to stimulate tissue growth.