Department of Cell BiologyMassachusetts General Hospital Cancer Center
Building 149, Room 7407
Charlestown, MA 02129
Lab Members: 4 postdoctoral fellows
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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, as well as multi-drug resistance in fungal infections.
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 cancers, 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 specific subunit (ARC105/MED15) of the Mediator co-activator, a large multi-protein 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 & Development 2010). Recent studies in the lab 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 may yield novel treatment modalities for nonalcoholic fatty liver diseases, which are precursors for hepatic inflammatory disease, cirrhosis, and hepatocellular carcinoma.
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 cholesterol efflux pump ABCA1 for translational repression. ABCA1 is important for high-density lipoprotein (HDL) synthesis and reverse cholesterol transport (RCT) from peripheral tissues, including macrophages/foam cells, and mutations/SNPs in the ABCA1 gene have been implicated in atherosclerosis. Moreover, our work has shown that miR-33a/b also control the expression of genes involved in fatty acid beta-oxidation and regulation of energy homeostasis. This demonstrates that miR-33a/b and their SREBP host genes act in concert to regulate cellular and animal metabolic homeostasis. Our findings suggest that miR-33a/b may represent novel targets of antisense-based therapeutics to increase ABCA1 levels, promote macrophage/foam cell cholesterol efflux, stimulate de novo HDL production and RCT, and ameliorate atherosclerosis/cardiovascular disease (Najafi-Shoushtari et al. Science 2010; Rottiers et al. CSH Symp. Quant. Biol. 2012).
We have 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). Our data indicate that SIRT1 can also be found in association with several other nuclear complexes with diverse roles in epigenetic regulation, senescence/aging, DNA damage control, and cancer processes, suggesting that the NAD+-dependent deacetylase activity of SIRT1 may integrate the energetic state of cells with regulation of diverse cellular processes.
Last Update: 8/22/2013