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

Abstract

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. is located on chromosome 15, and a natural hypomorphic mutation in the BALB/cJ 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 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.

Loss of liver-specific and sexually dimorphic gene expression by aryl hydrocarbon receptor activation in C57BL/6 mice

“…Mup s are located on chromosome 4 between 59,956,806 and 62,150,841 where 44 AhR enrichment peaks may be involved in their coordinated repression. The 1.6-fold inhibition of Zhx2 may also contribute to Mup repression [ 20 , 42 ].…”

Host Transcription Factors in Hepatitis B Virus RNA Synthesis

“…Zinc finger and homeoboxes 2 (ZHX2) is also a liver-enriched transcriptional repressor in adult hepatocytes and a tumor suppressor [265,266]. It is important for hepatocyte gene regulation and liver development and plays roles in renal cancer and stem cell differentiation [267][268][269][270]. ZHX2 contains four homeodomains and two C2H2 zinc finger motifs that allow for DNA binding causing transcriptional repression as both a homodimer ( Figure 3F) or a heterodimer when bound with ZHX1 [265,271].…”

In Contrast to Dietary Restriction, Application of Resveratrol in Mice Does not Alter Mouse Major Urinary Protein Expression

“…Remarkably, transcription of Zhx2, which, in a publication by Jiang [32], positively regulated transcription of various Mups including Mup20, was slightly increased in RSV-fed mice (p-value for CON-RSV 0.0256, Supplementary Figure S1). However, changes in Zhx2 did not coincide with changes in Mup mRNA levels.…”

“…Since ZHX2, IGF1, and GR may regulate MUP expression [13,30,32], we measured Zhx2 mRNA and protein levels, Igf1 mRNA levels and GR translocation into the nucleus in the liver of our mice. .…”

“…Various pathways putatively regulating MUP expression have been described. Its upregulation can be promoted by application of testosterone with thyroxine or growth hormone [30], appears to be controlled epigenetically [31] and was shown to be increased by zinc fingers and homeoboxes2 (Zhx2) in mouse liver [32]. Additionally, under DR, binding of glucocorticoid receptor (GR) to GR elements in Mup promotors could contribute to decreased Mup transcription [13,33].…”