PGC-1 Coactivator Activity Is Required for Murine Erythropoiesis

Abstract

Peroxisome proliferator-activated receptor gamma (PPARγ) coactivator 1α (PGC-1α) and PGC-1β have been shown to be intimately involved in the transcriptional regulation of cellular energy metabolism as well as other biological processes, but both coactivator proteins are expressed in many other tissues and organs in which their function is, in essence, unexplored. Here, we found that both PGC-1 proteins are abundantly expressed in maturing erythroid cells. PGC-1α and PGC-1β compound null mutant (Pgc-1^c) animals express less β-like globin mRNAs throughout development; consequently, neonatal Pgc-1^c mice exhibit growth retardation and profound anemia. Flow cytometry shows that the number of mature erythrocytes is markedly reduced in neonatal Pgc-1^c pups, indicating that erythropoiesis is severely compromised. Furthermore, hematoxylin and eosin staining revealed necrotic cell death and cell loss in Pgc-1^c livers and spleen. Chromatin immunoprecipitation studies revealed that both PGC-1α and -1β, as well as two nuclear receptors, TR2 and TR4, coordinately bind to the various globin gene promoters. In addition, PGC-1α and -1β can interact with TR4 to potentiate transcriptional activation. These data provide new insights into our understanding of globin gene regulation and raise the interesting possibility that the PGC-1 coactivators can interact with TR4 to elicit differential stage-specific effects on globin gene transcription.

SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.00247-14.

ACKNOWLEDGMENTS

We are grateful to many colleagues for helpful comments on the manuscript. We thank David Ginsburg and members of the Ginsburg laboratory for instructions in the use of their automated hematology analyzer.

We are grateful for support from the Jay and Betty Van Andel Foundation and Amway (China) Limited (H.E.X.), from the American Heart Association for a Scientist Development Grant (S.C.), and from NIH grants DK86956 and HL24415 (J.D.E. and O.T.), DK071662, DK066202, and HL089301 (H.E.X.), and DK077086 (J.D.L.).