Pruning of the Adipocyte Peroxisome Proliferator-Activated Receptor γ Cistrome by Hematopoietic Master Regulator PU.1

Abstract

“Master” transcription factors are the gatekeepers of lineage identity. As such, they have been a major focus of efforts to manipulate cell fate for therapeutic purposes. The ETS transcription factor PU.1 has a potent ability to confer macrophage phenotypes on cells already committed to a different lineage, but how it overcomes the presence of other master regulators is not known. The nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) is the master regulator of the adipose lineage, and its genomic binding pattern in adipocytes is well characterized. Here we show that, when expressed at macrophage levels in mature adipocytes, PU.1 bound a large fraction of its macrophage sites, where it induced chromatin opening and the expression of macrophage target genes. Strikingly, PU.1 markedly reduced the genomic binding of PPARγ without changing its abundance. PU.1 expression repressed genes with nearby adipocyte-specific PPARγ binding sites, while a common macrophage-adipocyte gene expression program was retained. Together, these data reveal unexpected lability within the adipocyte PPARγ cistrome and show that, even in terminally differentiated cells, PU.1 can remodel the cistrome of another master regulator.

SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.00599-13.

ACKNOWLEDGMENTS

We thank Michael Atchison (University of Pennsylvania) for the gift of a PU.1 expression construct. We thank Jonathan Schug, Alan Fox, Olga Smirnova and members of the Functional Genomics Core at the University of Pennsylvania Diabetes Research Center (DK19525) for ChIP-seq sample sequencing and running the Illumina pipeline. We also thank members of the Lazar lab for helpful discussions.

This work was supported by NIH DK49780 and by the Cell and Developmental Biology Training Grant (T32HD007516).