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Anders M. Naar, PhDProfessor of Cell BiologyHarvard Medical School
Assistant Cell BiologistCenter for Cancer Research
The Näär laboratory investigates the mechanisms by which genes are switched on or off and how these processes go awry in diseases such as cancers and cardio-metabolic disorders. For example, we have discovered previously unknown molecular mechanisms involved in controlling the output of genes important in cholesterol and fat metabolism. Studies of these mechanisms, involving a complex circuit of gene regulators and tiny snippets of RNA called microRNAs, are yielding new avenues in the development of therapeutic strategies to fight heart disease. We have also discovered a large multifunctional protein assembly that acts to prevent inappropriate activation of certain genes associated with development and several types of cancers. 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.
Anders M. Näär, PhDPrincipal Investigator
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 factorsPart 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 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 specific 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). 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.
MicroRNA regulation of cholesterol/lipid homeostasisCholesterol 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 yielded the surprising finding 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/single nucleotide polymorphisms 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, as well as the regulation of energy homeostasis (e.g., IRS2, AMPK and SIRT6). These results demonstrate 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).
SIRT1 epigenetic corepressor complexes in development and cancersWe have recently discovered that SIRT1 can be found in a large, epigenetic co-repressor complex with the LSD1 histone H3K4 demethylase and other chromatin-directed activities, and we have showed that this SIRT1-LSD1 complex functions to repress genes regulated by the Notch signaling pathway from Drosophila to mammals (Mulligan et al. Mol Cell 2011. This work may have important ramifications for our understanding of Notch regulation in cancers (e.g., T-ALL). In addition, our data indicate that SIRT1 can also be found in association with a number of 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.
A Postdoctoral Fellow position is available at the MGH Cancer Center/Harvard Medical School to investigate molecular mechanisms of gene regulation in normal cells and cancers. Our research is mainly focused on elucidating functions of the human ARC/Mediator family of transcriptional co-activator complexes in different gene expression pathways, such as SREBP regulation of cholesterol and lipids (see Yang et al. 2006, Nature 442:700-4), as well as the NF-kappaB regulator of inflammation and immunity. Other projects available in the Naar laboratory include exploring the role of the SIRT1 deacetylase in modulation of chromatin structures and gene expression programs governing metabolism, development and aging using model systems such as human cells, the worm Caenorhabditis elegans, and the fruitfly Drosophila melanogaster. We also investigate transcriptional programs involved in multidrug resistance (MDR) in S. cerevisiae and pathogenic fungi. These studies utilize both contemporary and state-of-the-art cellular, molecular, and biochemical strategies, such as small interfering RNA/RNAi technologies, whole genome expression analysis with Affymetrix DNA microarrays, chromatin immunoprecipitation (ChIP), tandem mass spectrometry, and high-throghput robotic screening for small-molecule inhibitors of gene regulatory pathways. We are also pursuing collaborative structural studies of activator/co-activator interactions using electron microscopy and NMR. Interested applicants should be highly motivated, have a Ph.D. or M.D. degree, a strong background in biochemistry, molecular biology, or cell biology, and publications in internationally recognized journals.
Please send a letter stating research interests, a curriculum vitae with past research experience, and contact information for 3 references to:
Anders M. Naar, PhDAssistant Professor of Cell BiologyHarvard Medical School and Massachusetts General HospitalCancer Center Building 149, 13th Street, Room 7407Charlestown, MA 02129 USAE-mail: firstname.lastname@example.org
Positions are available at the Massachusetts General Hospital Cancer Center/Harvard Medical School to investigate molecular mechanisms of Eeukaryotic transcriptional regulation. The Naar laboratory is pursuing a number of research directions, including elucidating functions of the human ARC/Mediator family of transcriptional co-activator complexes in different gene expression pathways, such as SREBP regulation of cholesterol and lipids (see Yang et al. Nature 442:700-4, 2006), as well as the NF-kappaB regulator of inflammation, immunity, and cancer. We are also investigating a novel nuclear receptor-like transcriptional program controlling multidrug resistance in S. cerevisiae and pathogenic fungi (e.g. Candida species) (see April 3rd issue of Nature; Thakur et al. Nature 452:604-609, 2008). Other projects available in the Naar laboratory include exploring conserved roles of the SIRT1 deacetylase in modulation of chromatin structure and gene expression programs governing lipid metabolism, differentiation and development, aging, and cancer. We have also identified several novel SIRT1 protein complexes that we are further characterizing using various biochemical and mammalian cell assays, as well as in vivo models such as the the roundworm Caenorhabditis elegans, the fruitfly Drosophila melanogaster, and mice. Our studies utilize both contemporary and state-of-the-art genetic/genomic, cellular, molecular, and biochemical strategies, such as small interfering RNA/RNAi technologies, whole genome expression analysis with Affymetrix DNA microarrays, chromatin immunoprecipitation (ChIP), protein affinity chromatography/tandem mass spectrometry, and high-throughput robotic screening for small-molecule inhibitors of gene regulatory pathways. We are also pursuing collaborative structural studies of activator/co-activator interactions using electron microscopy and NMR. Interested applicants should be highly motivated, have a PhD or MD degree, a strong background in molecular biology, biochemistry, or cell biology, and publications in internationally recognized journals.
Please send a letter describing your research interests, a curriculum vitae with past research experience, and contact information for at least 3 references to:
Anders M. Naar, PhDAssistant Professor of Cell BiologyHarvard Medical School and Massachusetts General HospitalCancer Center Building 149, 13th Street, Room 7407Charlestown, MA 02129 USA E-mail: email@example.com
View a list of publications by researchers at the Naar Laboratory
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