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Center for Cancer Research
Read Naar Lab Annual Report for 2017-2018
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 complex circuits of gene regulators and tiny snippets of RNA called microRNAs, are yielding new therapeutic strategies to target metabolic defects contributing to the etiology of many types of cancers as well as cardiometabolic diseases such as obesity, type 2 diabetes, non-alcoholic fatty liver diseases, and coronary artery disease.
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 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 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). 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 ﬁndings suggest that miR-33a/b may represent novel targets of antisense-based therapeutics to ameliorate cardiovascular disease (Najaﬁ-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 beneﬁcial 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 identiﬁcation 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).
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: email@example.com
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: firstname.lastname@example.org
View a list of publications by researchers at the Naar Laboratory
Nishikawa JL, Boeszoermenyi A, Vale-Silva LA, Torelli R, Posteraro B, Sohn YJ, Ji F, Gelev V, Sanglard D, Sanguinetti M, Sadreyev RI, Buhrlage SJ, Gray NS, Wagner G*, Näär AM*, and Arthanari H*. Inhibiting fungal multidrug resistance by disrupting an activator-Mediator interaction. Nature. 2016 Feb 25;530 (7591) :485-9.
Wagschal A, Najaﬁ-Shoushtari SH, Wang L, Goedeke L, Sinha S, Delemos AS, Black JC, Ramirez CM, Li X, Tewhey R, Hatoum I, Shah N, Kristo F, Psychogios N, Vrbanac V, Lu Y-C, Hla T, de Cabo R, Tsang JS, Schadt E, Sabeti PC, Kathiresan S, Cohen DE, Whetstine J, Chung RT, Fernández-Hernando C, Kaplan LM, Bernards A, Gerszten RE, and Näär AM. Genome-wide identiﬁcation of microRNAs regulating cholesterol/lipid homeostasis. Nature Medicine. 2015. Nov;21 (11) :1290-7.
Goedeke L, Aranda JF, Canfrán-Duque A, Rotllan N, Ramírez CM, Lin C-S, Araldi E, Anderson NN, Wagschal A, Cabo RD, Horton JD, Lasunción MA, Näär AM, Suárez Y and Fernández-Hernando C. Identiﬁcation of miR-148a as a novel regulator of cholesterol metabolism. Nature Medicine. 2015. Nov;21 (11) :1280-9.
Sedic M, Skibinski A, Brown N, Gallardo M, Mulligan P, Martinez P, Dake B, Glover E, Richardson A, Cowan J, Toland AE, Ravichandran K, Riethman H, Naber SP, Näär AM, Blasco MA, Hinds PW, and Kuperwasser C. Haploinsufficiency for BRCA1 leads to cell-type-speciﬁc genomic instability and premature senescence. Nature Communications. 2015 Jun 24;6:7505.
Rottiers V, Obad S, Petri A, McGarrah R, Lindholm MW, Black JC, Sinha S, Goody RJ, Lawrence MS, Delemos AS, Hansen HF, Whittaker S, Henry S, Brookes R, Najaﬁ-Shoushtari SH, Chung RT, Whetstine JW, Gerszten RE, Kauppinen S*, and Näär AM*. Pharmacological inhibition of a microRNA family in non-human primates by a seed-targeting 8-mer antimiR oligonucleotide. Science Translational Medicine. 2013 Nov 20;5(212):212ra162.
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