Major Research Areas
Hong Lu, PhD
- Assistant Professor of Pharmacology
Research Programs and Affiliations
- Biomedical Sciences Program
Education & Fellowships
- Fellowship: University of Kansas Medical Center, Kansas City, KS, 2006, Liver Pharmacology/Toxicology
- PhD: Rutgers University, 2002, Toxicology
- MS: Peking Union Med Coll, Beijing, China, 1997, Biochemical Pharmacology
Gene regulation during liver development and carcinogenesis
Drug metabolism, liver protection, liver-kidney comorbidity, cancer chemoprevention, and cancer therapy
As the metabolic center, liver is vital for the survival of the organism due to its critical role in nutrition and detoxification of xenobiotics and metabolic wastes. The incidence of steatohepatitis and liver cancer are increasing steadily in the USA due to the pandemic of obesity and metabolic syndrome and the increase in HCV infection. The major research interest of our laboratory is to understand the roles of key nuclear receptors (transcription factors) and epigenetics in regulating hepatic expression of genes important in drug processing, essential metabolic function, and carcinogenesis during normal liver development and the progression of steatohepatitis and carcinogenesis, so that we can develop more effective and safer drug treatments for patients.
Different from many other major cancers, primary liver cancer is the direct cause of death because liver is vital for the survival of the organism. Liver cancer is intrinsically resistant to cytotoxic drugs, and most liver cancer patients have markedly compromised liver function due to liver fibrosis/cirrhosis. Therefore, an ideal therapy for liver cancer should treat liver cancer and improve liver function simultaneously. Hepatocyte nuclear factor 4alpha (HNF4α) is a master regulator of liver development and function. HNF4α is also a well-established tumor suppressor. Deficiency of HNF4α is associated with various chronic liver diseases and liver cancer in patients. Multiline of evidence suggest that restoration of the expression and function of HNF4α can simultaneously improve liver function and inhibit liver carcinogenesis.
The regulation of hepatic gene expression by HNF4α is dependent on the access of HNF4α to open chromatins modulated by chromatin remodeling. SMARCB1 (SNF5) is a core subunit of SWI/SNF, a key chromatin remodeling complex. Mutations of SNF5 cause highly malignant rhabdoid tumors in humans. The total frequency of SWI/SNF mutations in human cancers is 20%, approaching that of p53 mutations. Loss of BRM and ARID1A subunits of SWI/SNF is frequent in human liver cancer. Both mouse and human tumors deficient in SNF5 have few, if any, other mutations, which leads to the conclusion that SNF5 deficiency is a key epigenetic driver in cancer. Utilizing a novel mouse model with tamoxifen-inducible liver-specific knockout of SNF5, we discovered a novel crucial role of SNF5 in maintaining hepatic chromatin architecture, gene expression, and metabolic function in adult liver. Interestingly, we found that disruption in the expression and function of HNF4α may play a key role in the deregulation of liver transcriptome and the pathogenesis of severe liver-kidney comorbidity developed in the SNF5 liver-specific knockout mice.
The central research interest of our laboratory is to understand how SNF5 and HNF4α work together to define hepatic epigenome and transcriptome during development, disease progression, and carcinogenesis in the developing and adult liver, and how the expression and activities of SNF5 and HNF4α are deregulated during liver diseases. The goal is to restore the activities of SNF5 and HNF4α to improve liver function and meanwhile prevent/treat liver cirrhosis and liver cancer in patients with chronic liver diseases.
We are using RNA-sequencing to elucidate changes of transcriptome in livers of wild-type mice and mice with inducible liver-specific knockout of SNF5 and HNF4α. We are using DNAse-sequencing and ChIP-sequencing to study dynamic changes of chromatin accessibility, epigenome (DNA methylation and histone modifications), and global DNA-binding of transcription factors. In this regard, we are integrating the in-house sequencing data with the public genome-wide sequencing data (e.g. the ENCODE project), coupled with in vitro luciferase reporter assay, as a highly efficient approach to understand the mechanism of gene regulation by SNF5 and HNF4α.
G-quadruplex (G4) is a thermodynamically highly stable 4-stranded helical structure formed in a single-stranded DNA or RNA. In recent years, G4 has emerged from being a "test-tube" structural curiosity, to being recognized as an important epigenetic mechanism for regulating multiple biological processes in vivo including DNA replication, transcription, RNA splicing, and translation. Interestingly, we identified G4 motifs in the 5' UTR of mouse and human HNF4a1 mRNAs. We are actively studying how the protein expression of HNF4α is regulated by G4. Meanwhile, we are studying the anticancer mechanism of G4 DNA oligos which have many interesting drug-like features. The long-term goal of our study is to develop novel therapy to treat liver cancer and improve liver function simultaneously, through restoring the protein expression and activity of master regulators of liver development and liver function.