Zhx2 (zinc fingers and homeoboxes 2) regulates major urinary protein gene expression in the mouse liver

J Biol Chem. 2017 Apr 21;292(16):6765-6774. doi: 10.1074/jbc.M116.768275. Epub 2017 Mar 3.


The mouse major urinary proteins (Mups) are encoded by a large family of highly related genes clustered on chromosome 4. Mups, synthesized primarily and abundantly in the liver and secreted through the kidneys, exhibit male-biased expression. Mups bind a variety of volatile ligands; these ligands, and Mup proteins themselves, influence numerous behavioral traits. Although urinary Mup protein levels vary between inbred mouse strains, this difference is most pronounced in BALB/cJ mice, which have dramatically low urinary Mup levels; this BALB/cJ trait had been mapped to a locus on chromosome 15. We previously identified Zhx2 (zinc fingers and homeoboxes 2) as a regulator of numerous liver-enriched genes. Zhx2 is located on chromosome 15, and a natural hypomorphic mutation in the BALB/cJ Zhx2 allele dramatically reduces Zhx2 expression. Based on these data, we hypothesized that reduced Zhx2 levels are responsible for lower Mup expression in BALB/cJ mice. Using both transgenic and knock-out mice along with in vitro assays, our data show that Zhx2 binds Mup promoters and is required for high levels of Mup expression in the adult liver. In contrast to previously identified Zhx2 targets that appear to be repressed by Zhx2, Mup genes are positively regulated by Zhx2. These data identify Zhx2 as a novel regulator of Mup expression and indicate that Zhx2 activates as well as represses expression of target genes.

Keywords: ChiP; development; hepatocyte; mouse genetics; transcription.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Alleles
  • Animals
  • Cell Line
  • Chromatin / metabolism
  • HEK293 Cells
  • Hep G2 Cells
  • Homeodomain Proteins / physiology*
  • Humans
  • Kidney / metabolism
  • Ligands
  • Liver / metabolism*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Promoter Regions, Genetic
  • Protein Binding
  • Proteins / physiology*
  • Transcription Factors / physiology*


  • Chromatin
  • Homeodomain Proteins
  • Ligands
  • Proteins
  • Transcription Factors
  • ZHX2 protein, human
  • Zhx2 protein, mouse
  • major urinary proteins