Liver-specific ablation of Krüppel-associated box-associated protein 1 in mice leads to male-predominant hepatosteatosis and development of liver adenoma.
The liver is characterized by sexually dimorphic gene expression translating into sex-specific differences in lipid, drug, steroid hormone, and xenobiotic metabolism, with distinct responses of males and females to environmental challenges. Here, we investigated the role of the Krüppel-associated box (KRAB)-associated protein 1 (KAP1) epigenetic regulator in this process. Liver-specific KAP1 knockout (KO) led to strikingly sexually dimorphic phenotypic disturbances, including male-predominant steatosis and hepatic tumors with up-regulation of protein kinase B and extracellular signal-related kinases 1/2 mitogen-activated protein kinase signaling. This correlated with the sex-specific transcriptional dysregulation of a wide range of metabolic genes, notably those involved in retinol and sex hormone processing as well as in detoxification. Furthermore, chromatin immunoprecipitation followed by deep sequencing indicated that a number of dysregulated genes are direct targets of the KRAB/KAP1 repression system. Those genes include sexually dimorphic cytochrome P 450 Cyp2d9, glutathione S-transferase π, Cyp2a, Cyp2b, and Cyp3a gene clusters. Additionally, we identified a male-restricted KAP1-binding site in the fat-specific protein 27 gene, correlating with its male-predominant up-regulation upon Kap1 deletion, suggesting that the latter might be an important trigger in the development of male-specific hepatosteatosis and secondary tumorigenesis.


CONCLUSIONS
This work reveals KRAB/KAP1-mediated transcriptional regulation as a central event in metabolic control hormones, drugs, and xenobiotics in the liver and further links disturbances in these processes with hepatic carcinogenesis.
School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
Karolina
K
Bojkowska
Fabio
F
Aloisio
Marco
M
Cassano
Adamandia
A
Kapopoulou
Francesca
F
Santoni de Sio
Nadine
N
Zangger
Sandra
S
Offner
Cristina
C
Cartoni
Charles
C
Thomas
Simon
S
Quenneville
Kai
K
Johnsson
Didier
D
Trono
D000236:Adenoma / Q000235:genetics* / Q000473:pathology; D000818:Animals; D001707:Biopsy, Needle; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000235:genetics* / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000378:metabolism*; D011897:Random Allocation; D012097:Repressor Proteins / Q000378:metabolism*; D012680:Sensitivity and Specificity; D012737:Sex Factors; D000076183:Tripartite Motif-Containing Protein 28; D016335:Zinc Fingers / Q000235:genetics
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; C103190:Trim28 protein, mouse; D000076183:Tripartite Motif-Containing Protein 28