Page 60 - ebook

[A. Biochemistry/Molecular Biology] A-30

Liver-specific deletion of mouse CTCF leads to hepatic

steatosis via augmented PPARγ signaling

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Woong-Jae Jung¹ , Min-Ji Song¹ , Yeeun Choi¹ , Hyoung-Pyo Kim¹*
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¹Department of Environmental Medical Biology, Yonsei University College of Medicine, Seoul 03722, Korea

The liver is the major organ for metabolizing lipids, and malfunction thereof leads to various diseases. Non-alcoholic
fatty liver disease (NAFLD) is rapidly becoming a major health concern worldwide and is characterized by abnormal

retention of excess lipids in the liver. CCCTC-binding factor (CTCF) is a highly conserved zinc finger protein that
regulates higher-order chromatin organization and is involved in various gene regulation processes. Here, we sought

to determine the physiological role of CTCF in hepatic lipid metabolism. We generated liver-specific CTCF-ablated
and/or CD36 whole-body knockout mice. Overexpression or knockdown of PPAR in the liver was achieved using

adenovirus. Mice were examined for development of hepatic steatosis and inflammation. RNA-seq was performed
to identify genes affected by CTCF depletion. Genome-wide occupancy of H3K27ac, PPARγ and CTCF were analyzed

by ChIP-seq. Genome-wide chromatin interactions were analyzed by in situ Hi-C. Global analysis of the transcriptome
and enhancer landscape revealed that CTCF-depleted liver exhibited enhanced accumulation of PPARγ in the nucleus,

which leads to increased expression of its downstream target genes, including fat storage-related gene CD36,
involved in lipid metabolic process. Hepatic steatosis developed in liver-specific CTCF-deficient mice was ameliorated

by repression of PPARγ via pharmacological blockade or adenovirus-mediated knockdown.