Regulator of sex-limitation KRAB zinc finger proteins modulate sex-dependent and -independent liver metabolism

Abstract

Krüppel-related zinc finger proteins (KRAB-zfps) comprise the largest mammalian transcription factor family, but their specific functions are largely unknown. Two KRAB-zfps, regulator of sex-limitation (Rsl) 1 and Rsl2, repress expression of the mouse sex-limited protein (Slp) gene, the hallmark of Rsl activity, as well as some other male-predominant liver genes. This phenotype suggests Rsl modifies sex-specific transcription. The scope of Rsl control was determined by expression profiling of liver RNA from wild-type (wt), rsl, and transgenic mice with hepatic overexpression of Rsl1 or Rsl2. About 7.5% of the liver transcriptome was Rsl-responsive. More genes in males than females were affected by the loss of Rsl (e.g., in rsl mice), whereas Rsl overexpression altered more transcripts in females than males. Rsl dramatically repressed some female-predominant genes, but most were modestly (1.25- to 2-fold) influenced. In males, most Rsl-responsive genes unexpectedly expressed at lower levels in rsl than wt, suggesting not all are direct targets of Rsl repression. Gene Ontology analysis showed Rsl targets enriched in pathways of cholesterol, steroid, and lipid metabolism, linking Rsl to energy balance. In accord with this, blood glucose levels were less in male rsl than wt mice, and less responsive to fasting and refeeding. rsl mice were also leaner than wt, consistent with their hepatic regulation of phosphoenolpyruvate carboxykinase 1 and stearoyl-Coenzyme A desaturase 1. Altogether, Rsl's effect on sexually dimorphic and metabolically sensitive liver gene expression suggests a role for KRAB-zfps as broad genetic modulators of individual adaptation.