title: The KRAB zinc finger protein RSL1 modulates sex-biased gene expression in liver and adipose tissue to maintain metabolic homeostasis.
abstract: Krüppel-associated box zinc finger proteins (KRAB-ZFPs) are a huge family of vertebrate-specific repressors that modify gene expression in an epigenetic manner. Despite a well-defined repression mechanism, few biological roles or gene targets of KRAB-ZFP are known. Regulator of sex-limitation 1 (RSL1) is a mouse KRAB-ZFP that enforces male-predominant expression in the liver, affecting body mass and pubertal timing. Here we show that female but not male Rsl1(-/-) mice gain more weight than wild-type mice on a high-fat diet (HFD) and that key liver and white adipose tissue (WAT) metabolic genes are altered in both Rsl1(-/-) sexes in response to dietary stress. Expression profiling of Rsl1-sensitive genes in liver and WAT indicates that RSL1 accentuates sex-biased gene expression in liver but greatly diminishes it in WAT. RSL1 expression solely in liver is sufficient to limit diet-induced weight gain and suppress lipogenic genes in WAT, indicating that RSL1 balances metabolism via liver-to-adipose-tissue communication. RSL1's effects on adult physiology exemplify a significant modulatory capacity of KRAB-ZFPs, in the absence of which there is widespread metabolic dysregulation. This ability to buffer against gene expression noise, coupled with extensive individual genetic variation, highlights the enormous potential of KRAB-Zfp genes as candidate risk factors for complex diseases.
authors.affiliation: Department of Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Krebs
authors.forename: Deqiang
authors.initials: D
authors.lastname: Zhang
authors.forename: Lei
authors.initials: L
authors.lastname: Yin
authors.forename: Diane M
authors.initials: DM
authors.lastname: Robins
mesh_terms: D052436:Adipose Tissue, White / Q000378:metabolism*; D000818:Animals; D059305:Diet, High-Fat / Q000009:adverse effects; D005260:Female; D005786:Gene Expression Regulation; D006706:Homeostasis; D050155:Lipogenesis; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D058977:Molecular Sequence Annotation; D009765:Obesity / Q000235:genetics / Q000378:metabolism; D009928:Organ Specificity; D012097:Repressor Proteins / Q000502:physiology*; D012727:Sex Characteristics; D013312:Stress, Physiological; D059467:Transcriptome
chemical_list: D012097:Repressor Proteins; C550540:Rsl1 protein, mouse