The Näär laboratory investigates the mechanisms by which genes are switched on or off and how these processes go awry in diseases such as cancer, cardiovascular disease, diabetes, and other metabolic disorders. We have discovered previously unknown molecular mechanisms involved in controlling the output of genes important in cholesterol and fat metabolism. Studies of these mechanisms, based on activities of the tiny snippets of RNA called microRNAs, are yielding new avenues in the development of therapeutic strategies to fight heart disease. We also have discovered a large multi-functional protein assembly that prevents certain genes associated with development and several types of cancers from being inappropriately activated. This is accomplished by changing the way DNA is packaged in the cell. Our current work is aimed at targeting this novel cellular process by small-molecule therapeutics to combat cancers.
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 several types of cancer, including breast and prostate malignancies, highlighting the importance of understanding how cholesterol/lipid homeostasis is controlled. Our work on the 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 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). We are now parlaying the detailed molecular understanding of the SREBP gene activation mechanism gained from these studies to develop novel therapeutics for the treatment of cholesterol/ metabolic disorders. Our recent studies have also uncovered a novel SREBP-regulatory feedback circuit linking production of the key membrane phospholipid phosphatidylcholine to SREBPdependent control of hepatic lipogenesis (Walker et al. Cell 2011). These insights may yield novel treatment modalities for nonalcoholic fatty liver diseases, which are precursors for hepatic inflammatory disease, cirrhosis, and hepatocellular carcinoma.
Cholesterol and lipids are trafficked in the blood as lipoprotein particles, such as low-density lipoprotein (LDL) and high-density lipoprotein (HDL) that 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 yielded the surprising finding that miR-33a/b target the ATP-binding cassette transporter ABCA1 for translational repression. ABCA1 is important for HDL synthesis and reverse cholesterol transport from peripheral tissues, including macrophages/ foam cells, and mutations/SNPs in the ABCA1 gene have been implicated in atherosclerosis. As SREBPs promote cholesterol uptake and synthesis through the transactivation of the LDL receptor and cholesterol biosynthesis genes, miR-33-mediated inhibition of ABCA1 and cholesterol efflux acts in cooperation with the SREBP host genes to boost intracellular cholesterol levels. This represents the first example of microRNA-host gene cooperativity in regulating a physiological pathway. Moreover, our findings suggest that miR-33 may represent a novel target of antisense-based therapeutics to increase ABCA1 levels, HDL production, and RCT, and ameliorate cardiovascular disease (Najafi-Shoushtari et al. Science 2010).
Our work has also been aimed at understanding the role of the NAD+-dependent deacetylase SIRT1 in controlling physiological and developmental processes conserved among metazoans. For example, our studies have revealed a critical role for SIRT1 orthologs in negative regulation of SREBPs during fasting from C. elegans to mammals, with important implications for human cholesterol/lipid disorders (Walker et al. Genes & Development 2010). In addition, we recently found that SIRT1 can be found in a large epigenetic co-repressor complex with the LSD1 histone H3K4 demethylase and other chromatin-directed activities, and showed that this SIRT1-LSD1 complex functions to repress genes regulated by the Notch signaling pathway from Drosophila to mammals (Mulligan et al. Molecular Cell 2011). This work may have important ramifications for our understanding of Notch regulation in cancers (e.g., T-ALL).