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Mitchell A. Lazar

Joseph Bass, Mitchell A Lazar
Biological clocks are autonomous anticipatory oscillators that play a critical role in the organization and information processing from genome to whole organisms. Transformative advances into the clock system have opened insight into fundamental mechanisms through which clocks program energy transfer from sunlight into organic matter and potential energy, in addition to cell development and genotoxic stress response. The identification of clocks in nearly every single cell of the body raises questions as to how this gives rise to rhythmic physiology in multicellular organisms and how environmental signals entrain clocks to geophysical time...
November 25, 2016: Science
Romeo Papazyan, Zheng Sun, Yong Hoon Kim, Paul M Titchenell, David A Hill, Wenyun Lu, Manashree Damle, Min Wan, Yuxiang Zhang, Erika R Briggs, Joshua D Rabinowitz, Mitchell A Lazar
Liver fat accumulation precedes non-alcoholic steatohepatitis, an increasing cause of end-stage liver disease. Histone deacetylase 3 (HDAC3) is required for hepatic triglyceride homeostasis, and sterol regulatory element binding protein (SREBP) regulates the lipogenic response to feeding, but the crosstalk between these pathways is unknown. Here we show that inactivation of SREBP by hepatic deletion of SREBP cleavage activating protein (SCAP) abrogates the increase in lipogenesis caused by loss of HDAC3, but fatty acid oxidation remains defective...
November 10, 2016: Cell Metabolism
Giulia Ferrannini, Maria Namwanje, Bin Fang, Manashree Damle, Dylan Li, Qiongming Liu, Mitchell A Lazar, Li Qiang
OBJECTIVE: Genetic background largely contributes to the complexity of metabolic responses and dysfunctions. Induction of brown adipose features in white fat, known as brown remodeling, has been appreciated as a promising strategy to offset the positive energy balance in obesity and further to improve metabolism. Here we address the effects of genetic background on this process. METHODS: We investigated browning remodeling in a depot-specific manner by comparing the response of C57BL/6J, 129/Sv and FVB/NJ mouse strains to cold...
October 2016: Molecular Metabolism
Yuxiang Zhang, Bin Fang, Manashree Damle, Dongyin Guan, Zhenghui Li, Yong Hoon Kim, Maureen Gannon, Mitchell A Lazar
Hepatocyte nuclear factor 6 (HNF6) is required for liver development, but its role in adult liver metabolism is not known. Here we show that deletion of HNF6 in livers of adult C57Bl/6 mice leads to hepatic steatosis in mice fed normal laboratory chow. Although HNF6 is known mainly as a transcriptional activator, hepatic loss of HNF6 up-regulated many lipogenic genes bound directly by HNF6. Many of these genes are targets of the circadian nuclear receptor Rev-erbα, and binding of Rev-erbα at these sites was lost when HNF6 was ablated in the liver...
July 15, 2016: Genes & Development
Kevin D Pereira, Cindy K Jon, Peter Szmuk, Rande H Lazar, Ron B Mitchell
The management of sleep disordered breathing (SDB) in children differs between institutions, and there is a need for an updated review of current practice. Literature was reviewed using the PubMed database from 1995 to 2015 by four tertiary care providers experienced in the management of children with SDB. Articles were selected for clinical applicability, strength of evidence, and practicality for practicing clinicians. Fifty-five articles were identified by tertiary care providers in pediatric anesthesiology, pediatric pulmonology, sleep medicine, and pediatric otolaryngology...
July 2016: Ear, Nose, & Throat Journal
J Wayne Lazar
This article contrasts two American Physiological Societies, one founded near the beginning of the nineteenth century in 1837 and the other founded near its end in 1887. The contrast allows a perspective on how much budding neuroscience had developed during the nineteenth century in America. The contrast also emphasizes the complicated structure needed in both medicine and physiology to allow neurophysiology to flourish. The objectives of the American Physiological Society of 1887 were (and are) to promote physiological research and to codify physiology as a discipline...
July 5, 2016: Journal of the History of the Neurosciences
Xin Teng, Matthew J Emmett, Mitchell A Lazar, Erwin Goldberg, Joshua D Rabinowitz
Metabolomics is a valuable tool for studying tissue- and organism-specific metabolism. In normal mouse testis, we found 70 μM S-2-hydroxyglutarate (2HG), more than 10-fold greater than in other tissues. S-2HG is a competitive inhibitor of α-ketoglutarate-dependent demethylation enzymes and can alter histone or DNA methylation. To identify the source of testis S-2HG, we fractionated testis extracts and identified the fractions that actively produced S-2HG. Through a combination of ion exchange and size exclusion chromatography, we enriched a single active protein, the lactate dehydrogenase isozyme LDHC, which is primarily expressed in testis...
September 16, 2016: ACS Chemical Biology
Liguo Zhang, Xuelian He, Lei Liu, Minqing Jiang, Chuntao Zhao, Haibo Wang, Danyang He, Tao Zheng, Xianyao Zhou, Aishlin Hassan, Zhixing Ma, Mei Xin, Zheng Sun, Mitchell A Lazar, Steven A Goldman, Eric N Olson, Q Richard Lu
No abstract text is available yet for this article.
June 20, 2016: Developmental Cell
David R Raleigh, David A Solomon, Shane A Lloyd, Ann Lazar, Michael A Garcia, Penny K Sneed, Jennifer L Clarke, Michael W McDermott, Mitchel S Berger, Tarik Tihan, Daphne A Haas-Kogan
BACKGROUND: Pineal parenchymal tumors (PPTs) are rare neoplasms of the central nervous system, and data concerning clinical outcomes are limited. The purpose of this study was to define the clinical behavior of PPT according to current histopathologic criteria and identify prognostic factors to guide therapeutic decisions. METHODS: Seventy-five patients treated for PPT at a single institution between 1992 and 2015 were retrospectively identified. Forty-five resection specimens were available and re-reviewed...
June 9, 2016: Neuro-oncology
Jennifer Jager, Fenfen Wang, Bin Fang, Hee-Woong Lim, Lindsey C Peed, David J Steger, Kyoung-Jae Won, Alexei Kharitonenkov, Andrew C Adams, Mitchell A Lazar
FGF21 is an atypical member of the FGF family that functions as a hormone to regulate carbohydrate and lipid metabolism. Here we demonstrate that the actions of FGF21 in mouse adipose tissue, but not in liver, are modulated by the nuclear receptor Rev-erbα, a potent transcriptional repressor. Interrogation of genes induced in the absence of Rev-erbα for Rev-erbα-binding sites identified βKlotho, an essential coreceptor for FGF21, as a direct target gene of Rev-erbα in white adipose tissue but not liver...
May 13, 2016: Journal of Biological Chemistry
Liguo Zhang, Xuelian He, Lei Liu, Minqing Jiang, Chuntao Zhao, Haibo Wang, Danyang He, Tao Zheng, Xianyao Zhou, Aishlin Hassan, Zhixing Ma, Mei Xin, Zheng Sun, Mitchell A Lazar, Steven A Goldman, Eric N Olson, Q Richard Lu
Establishment and maintenance of CNS glial cell identity ensures proper brain development and function, yet the epigenetic mechanisms underlying glial fate control remain poorly understood. Here, we show that the histone deacetylase Hdac3 controls oligodendrocyte-specification gene Olig2 expression and functions as a molecular switch for oligodendrocyte and astrocyte lineage determination. Hdac3 ablation leads to a significant increase of astrocytes with a concomitant loss of oligodendrocytes. Lineage tracing indicates that the ectopic astrocytes originate from oligodendrocyte progenitors...
February 8, 2016: Developmental Cell
Yi Wang, David B Frank, Michael P Morley, Su Zhou, Xiaoru Wang, Min Min Lu, Mitchell A Lazar, Edward E Morrisey
The terminal stages of pulmonary development, called sacculation and alveologenesis, involve both differentiation of distal lung endoderm progenitors and extensive cellular remodeling of the resultant epithelial lineages. These processes are coupled with dramatic expansion of distal airspace and surface area. Despite the importance of these late developmental processes and their relation to neonatal respiratory diseases, little is understood about the molecular and cellular pathways critical for their successful completion...
February 8, 2016: Developmental Cell
Alexander Teumer, Adrienne Tin, Rossella Sorice, Mathias Gorski, Nan Cher Yeo, Audrey Y Chu, Man Li, Yong Li, Vladan Mijatovic, Yi-An Ko, Daniel Taliun, Alessandro Luciani, Ming-Huei Chen, Qiong Yang, Meredith C Foster, Matthias Olden, Linda T Hiraki, Bamidele O Tayo, Christian Fuchsberger, Aida Karina Dieffenbach, Alan R Shuldiner, Albert V Smith, Allison M Zappa, Antonio Lupo, Barbara Kollerits, Belen Ponte, Bénédicte Stengel, Bernhard K Krämer, Bernhard Paulweber, Braxton D Mitchell, Caroline Hayward, Catherine Helmer, Christa Meisinger, Christian Gieger, Christian M Shaffer, Christian Müller, Claudia Langenberg, Daniel Ackermann, David Siscovick, Eric Boerwinkle, Florian Kronenberg, Georg B Ehret, Georg Homuth, Gerard Waeber, Gerjan Navis, Giovanni Gambaro, Giovanni Malerba, Gudny Eiriksdottir, Guo Li, H Erich Wichmann, Harald Grallert, Henri Wallaschofski, Henry Völzke, Herrmann Brenner, Holly Kramer, I Mateo Leach, Igor Rudan, Hans L Hillege, Jacques S Beckmann, Jean Charles Lambert, Jian'an Luan, Jing Hua Zhao, John Chalmers, Josef Coresh, Joshua C Denny, Katja Butterbach, Lenore J Launer, Luigi Ferrucci, Lyudmyla Kedenko, Margot Haun, Marie Metzger, Mark Woodward, Matthew J Hoffman, Matthias Nauck, Melanie Waldenberger, Menno Pruijm, Murielle Bochud, Myriam Rheinberger, Niek Verweij, Nicholas J Wareham, Nicole Endlich, Nicole Soranzo, Ozren Polasek, Pim van der Harst, Peter Paul Pramstaller, Peter Vollenweider, Philipp S Wild, Ron T Gansevoort, Rainer Rettig, Reiner Biffar, Robert J Carroll, Ronit Katz, Ruth J F Loos, Shih-Jen Hwang, Stefan Coassin, Sven Bergmann, Sylvia E Rosas, Sylvia Stracke, Tamara B Harris, Tanguy Corre, Tanja Zeller, Thomas Illig, Thor Aspelund, Toshiko Tanaka, Uwe Lendeckel, Uwe Völker, Vilmundur Gudnason, Vincent Chouraki, Wolfgang Koenig, Zoltan Kutalik, Jeffrey R O'Connell, Afshin Parsa, Iris M Heid, Andrew D Paterson, Ian H de Boer, Olivier Devuyst, Jozef Lazar, Karlhans Endlich, Katalin Susztak, Johanne Tremblay, Pavel Hamet, Howard J Jacob, Carsten A Böger, Caroline S Fox, Cristian Pattaro, Anna Köttgen
Elevated concentrations of albumin in the urine, albuminuria, are a hallmark of diabetic kidney disease and are associated with an increased risk for end-stage renal disease and cardiovascular events. To gain insight into the pathophysiological mechanisms underlying albuminuria, we conducted meta-analyses of genome-wide association studies and independent replication in up to 5,825 individuals of European ancestry with diabetes and up to 46,061 without diabetes, followed by functional studies. Known associations of variants in CUBN, encoding cubilin, with the urinary albumin-to-creatinine ratio (UACR) were confirmed in the overall sample (P = 2...
March 2016: Diabetes
Brian J Altman, Annie L Hsieh, Arjun Sengupta, Saikumari Y Krishnanaiah, Zachary E Stine, Zandra E Walton, Arvin M Gouw, Anand Venkataraman, Bo Li, Pankuri Goraksha-Hicks, Sharon J Diskin, David I Bellovin, M Celeste Simon, Jeffrey C Rathmell, Mitchell A Lazar, John M Maris, Dean W Felsher, John B Hogenesch, Aalim M Weljie, Chi V Dang
The MYC oncogene encodes MYC, a transcription factor that binds the genome through sites termed E-boxes (5'-CACGTG-3'), which are identical to the binding sites of the heterodimeric CLOCK-BMAL1 master circadian transcription factor. Hence, we hypothesized that ectopic MYC expression perturbs the clock by deregulating E-box-driven components of the circadian network in cancer cells. We report here that deregulated expression of MYC or N-MYC disrupts the molecular clock in vitro by directly inducing REV-ERBα to dampen expression and oscillation of BMAL1, and this could be rescued by knockdown of REV-ERB...
December 1, 2015: Cell Metabolism
Bin Fang, Mitchell A Lazar
Circadian clocks maintain whole-body metabolic homeostasis by coordinating rhythmic gene expression in multiple tissues. Core clock regulators sustain their own oscillation and confer expression rhythmicity on clock-controlled genes (CCGs). Our unbiased examination of enhancer RNA (eRNA) transcription around the clock in mouse liver identified functional enhancers of circadian genes driven by phase-specific transcription factors (TFs). Rev-erbα emerged as a primary driver of circadian enhancers, leading to oscillating gene expression in opposite phases through direct and indirect regulation...
2015: Cold Spring Harbor Symposia on Quantitative Biology
Raymond E Soccio, Eric R Chen, Satyajit R Rajapurkar, Pegah Safabakhsh, Jill M Marinis, Joanna R Dispirito, Matthew J Emmett, Erika R Briggs, Bin Fang, Logan J Everett, Hee-Woong Lim, Kyoung-Jae Won, David J Steger, Ying Wu, Mete Civelek, Benjamin F Voight, Mitchell A Lazar
SNPs affecting disease risk often reside in non-coding genomic regions. Here, we show that SNPs are highly enriched at mouse strain-selective adipose tissue binding sites for PPARγ, a nuclear receptor for anti-diabetic drugs. Many such SNPs alter binding motifs for PPARγ or cooperating factors and functionally regulate nearby genes whose expression is strain selective and imbalanced in heterozygous F1 mice. Moreover, genetically determined binding of PPARγ accounts for mouse strain-specific transcriptional effects of TZD drugs, providing proof of concept for personalized medicine related to nuclear receptor genomic occupancy...
July 2, 2015: Cell
Daniel M Cohen, Kyoung-Jae Won, Nha Nguyen, Mitchell A Lazar, Christopher S Chen, David J Steger
A well-established cascade of transcription factor (TF) activity orchestrates adipogenesis in response to chemical cues, yet how cell-intrinsic determinants of differentiation such as cell shape and/or seeding density inform this transcriptional program remain enigmatic. Here, we uncover a novel mechanism licensing transcription in human mesenchymal stem cells (hMSCs) adipogenically primed by confluence. Prior to adipogenesis, confluency promotes heterodimer recruitment of the bZip TFs C/EBPβ and ATF4 to a non-canonical C/EBP DNA sequence...
2015: ELife
Yuxiang Zhang, Bin Fang, Matthew J Emmett, Manashree Damle, Zheng Sun, Dan Feng, Sean M Armour, Jarrett R Remsberg, Jennifer Jager, Raymond E Soccio, David J Steger, Mitchell A Lazar
Circadian and metabolic physiology are intricately intertwined, as illustrated by Rev-erbα, a transcription factor (TF) that functions both as a core repressive component of the cell-autonomous clock and as a regulator of metabolic genes. Here, we show that Rev-erbα modulates the clock and metabolism by different genomic mechanisms. Clock control requires Rev-erbα to bind directly to the genome at its cognate sites, where it competes with activating ROR TFs. By contrast, Rev-erbα regulates metabolic genes primarily by recruiting the HDAC3 co-repressor to sites to which it is tethered by cell type-specific transcription factors...
June 26, 2015: Science
David I Kline, Lida Teneva, Claudine Hauri, Kenneth Schneider, Thomas Miard, Aaron Chai, Malcolm Marker, Rob Dunbar, Ken Caldeira, Boaz Lazar, Tanya Rivlin, Brian Gregory Mitchell, Sophie Dove, Ove Hoegh-Guldberg
Understanding the temporal dynamics of present thermal and pH exposure on coral reefs is crucial for elucidating reef response to future global change. Diel ranges in temperature and carbonate chemistry parameters coupled with seasonal changes in the mean conditions define periods during the year when a reef habitat is exposed to anomalous thermal and/or pH exposure. Anomalous conditions are defined as values that exceed an empirically estimated threshold for each variable. We present a 200-day time series from June through December 2010 of carbonate chemistry and environmental parameters measured on the Heron Island reef flat...
2015: PloS One
Hee-Woong Lim, N Henriette Uhlenhaut, Alexander Rauch, Juliane Weiner, Sabine Hübner, Norbert Hübner, Kyoung-Jae Won, Mitchell A Lazar, Jan Tuckermann, David J Steger
Glucocorticoids (GCs) are commonly prescribed drugs, but their anti-inflammatory benefits are mitigated by metabolic side effects. Their transcriptional effects, including tissue-specific gene activation and repression, are mediated by the glucocorticoid receptor (GR), which is known to bind as a homodimer to a palindromic DNA sequence. Using ChIP-exo in mouse liver under endogenous corticosterone exposure, we report here that monomeric GR interaction with a half-site motif is more prevalent than homodimer binding...
June 2015: Genome Research
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