Regulation of the <i>F11, Klkb1, Cyp4v3</i> Gene Cluster in Livers of Metabolically Challenged Mice

<div><p>Single nucleotide polymorphisms (SNPs) in a 4q35.2 locus that harbors the coagulation factor XI (<i>F11</i>), prekallikrein (<i>KLKB1</i>), and a cytochrome P450 family member (<i>CYP4V2</i>) genes are associated with deep venous thrombosis (DVT). These SNPs exert their effect on DVT by modifying the circulating levels of FXI. However, SNPs associated with DVT were not necessarily all in <i>F11</i>, but also in <i>KLKB1</i> and <i>CYP4V2</i>. Here, we searched for evidence for common regulatory elements within the 4q35.2 locus, outside the <i>F11</i> gene, that might control FXI plasma levels and/or DVT risk. To this end, we investigated the regulation of the orthologous mouse gene cluster under several metabolic conditions that impact mouse hepatic <i>F11</i> transcription. In livers of mice in which HNF4α, a key transcription factor controlling <i>F11</i>, was ablated, or reduced by siRNA, a strong decrease in hepatic <i>F11</i> transcript levels was observed that correlated with <i>Cyp4v3</i> (mouse orthologue of <i>CYP4V2</i>), but not by <i>Klkb1</i> levels. Estrogens induced hepatic <i>F11</i> and <i>Cyp4v3</i>, but not <i>Klkb1</i> transcript levels, whereas thyroid hormone strongly induced hepatic <i>F11</i> transcript levels, and reduced <i>Cyp4v3</i>, leaving <i>Klkb1</i> levels unaffected. Mice fed a high-fat diet also had elevated <i>F11</i> transcription, markedly paralleled by an induction of <i>Klkb1 and Cyp4v3</i> expression. We conclude that within the mouse <i>F11</i>, <i>Klkb1</i>, <i>Cyp4v3</i> gene cluster, <i>F11</i> and <i>Cyp4v3</i> frequently display striking parallel transcriptional responses suggesting the presence of shared regulatory elements. </p>