Our research is focused on elucidating molecular mechanisms of gene regulation, with emphasis on disease-associated pathways contributing to cholesterol/lipid disorders, certain types of cancers, and multidrug resistance in fungal infections.
Cholesterol/lipid regulation by the SREBP transcription factors
Part of our effort is centered on understanding how transcriptional regulators activate or repress target gene expression. One area of interest concerns the regulatory circuits governing cholesterol/lipid homeostasis. Aberrant regulation of cholesterol and other lipids contributes to major human diseases such as atherosclerosis, type 2 diabetes, metabolic syndrome, Alzheimer’s disease, and many types of cancers, thus highlighting the importance of understanding how cholesterol/lipid homeostasis is controlled. Our work on the sterol regulatory element-binding protein (SREBP) transcription factor family, master regulators of cholesterol/lipid biosynthesis and metabolism, has provided key mechanistic insights into gene regulatory pathways guiding metabolic homeostasis. For example, we have found that a speci?c subunit (ARC105/MED15) of the Mediator co-activator, a large multiprotein assembly, plays a critical role in mediating SREBP-dependent activation of genes controlling cholesterol/ lipid homeostasis (Yang et al. Nature 2006). Our studies have also revealed a critical role for orthologs of the NAD+-dependent deacetylase SIRT1 in negative regulation of SREBPs during fasting from C. elegans to mammals, with important implications for human cholesterol/lipid disorders (Walker et al. Genes Dev 2010). We have also uncovered a novel SREBP-regulatory feedback circuit linking production of the key membrane phospholipid phosphatidylcholine to SREBP-dependent control of hepatic lipogenesis (Walker et al. Cell 2011). These insights together may yield novel treatments for cardiometabolic diseases and cancers.
MicroRNA regulation of cholesterol/lipid homeostasis
Cholesterol and lipids are trafficked in the blood as lipoprotein particles, such as low-density lipoprotein (LDL) and high-density lipoprotein (HDL), which ferry their fatty cargo to different cells and tissues. Intriguingly, we have found conserved microRNAs (miR-33a/b) embedded within intronic sequences in the human SREBP genes. Our studies revealed that miR-33a/b target the cholesterol efflux pump ABCA1 for translational repression. ABCA1 is important for HDL synthesis and reverse cholesterol transport (RCT) from peripheral tissues, including macrophages/foam cells, and mutations in the ABCA1 gene have been implicated in atherosclerosis. These ?ndings suggest that miR-33a/b may represent novel targets of antisense-based therapeutics to ameliorate cardiovascular disease (Naja?-Shoushtari et al. Science 2010; Rottiers et al. CSH Symp Quant Biol 2012; Rottiers & Näär, Nature Rev. Mol. Cell Biol. 2012; Rottiers et al. Science Transl Med 2013).
We have pioneered a systematic and multi-pronged approach to comprehensively determine the roles of microRNAs and other noncoding RNAs in metabolic control and contribution to cardiometabolic diseases. Our analysis of GWAS in >188,000 people uncovered several microRNAs associated with cardiometabolic abnormalities. We have demonstrated that two of these microRNAs, miR-128-1 and miR-148a, control HDL-cholesterol and low-density lipoprotein-cholesterol (LDL-C) through direct regulation of ABCA1 and LDL receptor (LDLR) expression, respectively. Moreover, our in vivo studies show that LNA antimiRs directed against these microRNAs led to upregulation of the LDLR and ABCA1 in liver, with a concomitant bene?cial decrease in circulating LDL-C and increased HDL-C. Results from these studies indicate that microRNAs may indeed represent novel therapeutic targets for the treatment of cardiovascular disease (Wagschal et al., Nature Medicine 2015; Goedeke et al. Nature Medicine 2015).
Multidrug resistance in pathogenic fungi
Immunocompromised individuals, such as cancer patients undergoing chemotherapy are highly susceptible to fungal infections (e.g., Candida species), which frequently become drug-resistant upon antifungal treatment. We have elucidated the molecular mechanism by which the important human pathogenic fungus Candida glabrata becomes resistant to standard azole antifungal treatment (Thakur et al. Nature 2008). Our work has led to the identi?cation of a potent inhibitor of multidrug resistance (MDR) in C. glabrata. This compound exhibits efficacy in mouse models as a novel anti-MDR co-therapeutic to re- sensitize drug-resistant C. glabrata to standard azole treatment (Nishikawa et al. Nature 2016).