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University of Massachusetts Medical School

Cellular and Molecular Physiology

University of Massachusetts Medical School Faculty Publications

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Phosphorylation On Pstp Controls Cell Wall Metabolism And Antibiotic Tolerance In Mycobacterium Smegmatis, Farah Shamma, Kadamba Papavinasasundaram, Aditya Bandekar, Christopher M. Sassetti, Cara C. Boutte Oct 2019

Phosphorylation On Pstp Controls Cell Wall Metabolism And Antibiotic Tolerance In Mycobacterium Smegmatis, Farah Shamma, Kadamba Papavinasasundaram, Aditya Bandekar, Christopher M. Sassetti, Cara C. Boutte

University of Massachusetts Medical School Faculty Publications

The mycobacterial cell wall is a dynamic structure that protects Mycobacterium tuberculosis and its relatives from environmental stresses. Modulation of cell wall metabolism under stress is thought to be responsible for decreased cell wall permeability and increased tolerance to antibiotics. The signaling pathways that control cell wall metabolism under stress, however, are poorly understood. Here, we examine the signaling capacity of a cell wall master regulator, the Serine Threonine Phosphatase PstP, in the model organism Mycobacterium smegmatis. We studied how interference with a regulatory phosphorylation site on PstP affects growth, cell wall metabolism and antibiotic tolerance. We find that a ...


Neural Jnk3 Regulates Blood Flow Recovery After Hindlimb Ischemia In Mice Via An Egr1/Creb1 Axis, Shashi Kant, Siobhan M. Craige, Kai Chen, Michaella M. Reif, Heather Learnard, Mark Kelly, Amada D. Caliz, Khanh-Van T. Tran, Kasmir Ramo, Owen M. Peters, Marc R. Freeman, Roger J. Davis, John F. Keaney Jr. Sep 2019

Neural Jnk3 Regulates Blood Flow Recovery After Hindlimb Ischemia In Mice Via An Egr1/Creb1 Axis, Shashi Kant, Siobhan M. Craige, Kai Chen, Michaella M. Reif, Heather Learnard, Mark Kelly, Amada D. Caliz, Khanh-Van T. Tran, Kasmir Ramo, Owen M. Peters, Marc R. Freeman, Roger J. Davis, John F. Keaney Jr.

University of Massachusetts Medical School Faculty Publications

Diseases related to impaired blood flow such as peripheral artery disease (PAD) impact nearly 10 million people in the United States alone, yet patients with clinical manifestations of PAD (e.g., claudication and limb ischemia) have limited treatment options. In ischemic tissues, stress kinases such as c-Jun N-terminal kinases (JNKs), are activated. Here, we show that inhibition of the JNK3 (Mapk10) in the neural compartment strikingly potentiates blood flow recovery from mouse hindlimb ischemia. JNK3 deficiency leads to upregulation of growth factors such as Vegfa, Pdgfb, Pgf, Hbegf and Tgfb3 in ischemic muscle by activation of the transcription factors Egr1 ...


Expression Of Mitochondrial Membrane-Linked Sab Determines Severity Of Sex-Dependent Acute Liver Injury, Sanda Win, Robert W. M. Min, Christopher Q. Chen, Jun Zhang, Yibu Chen, Meng Li, Ayako Suzuki, Manal F. Abdelmalek, Ying Wang, Mariam Aghajan, Filbert W. M. Aung, Anna Mae Diehl, Roger J. Davis, Tin A. Than, Neil Kaplowitz Sep 2019

Expression Of Mitochondrial Membrane-Linked Sab Determines Severity Of Sex-Dependent Acute Liver Injury, Sanda Win, Robert W. M. Min, Christopher Q. Chen, Jun Zhang, Yibu Chen, Meng Li, Ayako Suzuki, Manal F. Abdelmalek, Ying Wang, Mariam Aghajan, Filbert W. M. Aung, Anna Mae Diehl, Roger J. Davis, Tin A. Than, Neil Kaplowitz

University of Massachusetts Medical School Faculty Publications

SAB is an outer membrane docking protein for JNK mediated impaired mitochondrial function. Deletion of Sab in hepatocytes inhibits sustained JNK activation and cell death. Current work demonstrated that increasing SAB enhanced the severity of APAP liver injury. Female mice were resistant to liver injury and exhibited markedly decreased hepatic SAB protein expression versus males. The mechanism of SAB repression involved a pathway from ERalpha to p53 expression which induced miR34a-5p. miR34a-5p targeted the Sab mRNA coding region, repressing SAB expression. Fulvestrant or p53 knockdown decreased miR34a-5p and increased SAB in females leading to increased injury from APAP and TNF ...


Mtf1, A Classic Metal Sensing Transcription Factor, Promotes Myogenesis In Response To Copper, Cristina Tavera-Montañez, Sarah J. Hainer, Daniella Cangussu, Shellaina J. V. Gordon, Yao Xiao, Pablo Reyes-Gutierrez, Anthony N. Imbalzano, Juan G. Navea, Thomas G. Fazzio, Teresita Padilla-Benavides Jun 2019

Mtf1, A Classic Metal Sensing Transcription Factor, Promotes Myogenesis In Response To Copper, Cristina Tavera-Montañez, Sarah J. Hainer, Daniella Cangussu, Shellaina J. V. Gordon, Yao Xiao, Pablo Reyes-Gutierrez, Anthony N. Imbalzano, Juan G. Navea, Thomas G. Fazzio, Teresita Padilla-Benavides

University of Massachusetts Medical School Faculty Publications

MTF1 is a conserved metal-binding transcription factor in eukaryotes that binds to conserved DNA sequence motifs, termed metal response elements (MREs). MTF1 responds to metal excess and deprivation, protects cells from oxidative and hypoxic stresses, and is required for embryonic development in vertebrates. We used multiple strategies to identify an unappreciated role for MTF1 and copper (Cu) in cell differentiation. Upon initiation of myogenesis from primary myoblasts, MTF1 expression increased, as did nuclear localization. Mtf1 knockdown impaired differentiation, while addition of non-toxic concentrations of Cu+ enhanced MTF1 expression and promoted myogenesis. Cu+ bound stoichiometrically to a C-terminus tetra-cysteine of MTF1 ...


Brg1 Is A Prognostic Indicator And A Potential Therapeutic Target For Prostate Cancer, Rohini Muthuswami, Leeann Bailey, Radhakrishnan Rakesh, Anthony N. Imbalzano, Jeffrey A. Nickerson, Joel W. Hockensmith Jan 2019

Brg1 Is A Prognostic Indicator And A Potential Therapeutic Target For Prostate Cancer, Rohini Muthuswami, Leeann Bailey, Radhakrishnan Rakesh, Anthony N. Imbalzano, Jeffrey A. Nickerson, Joel W. Hockensmith

University of Massachusetts Medical School Faculty Publications

Brahma-related gene 1 (BRG1) is one of two mutually exclusive ATPases that function as the catalytic subunit of human SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeling enzymes. BRG1 has been identified as a tumor suppressor in some cancer types but has been shown to be expressed at elevated levels, relative to normal tissue, in other cancers. Using TCGA (The Cancer Genome Atlas) prostate cancer database, we determined that BRG1 mRNA and protein expression is elevated in prostate tumors relative to normal prostate tissue. Only 3 of 491 (0.6%) sequenced tumors showed amplification of the locus or mutation in the ...


A Persistence Detector For Metabolic Network Rewiring In An Animal, Jote T. Bulcha, Gabrielle E. Giese, Zulfikar Ali, Yong-Uk Lee, Melissa D. Walker, Amy D. Holdorf, L. Safak Yilmaz, Robert C. Brewster, Albertha J. M. Walhout Aug 2018

A Persistence Detector For Metabolic Network Rewiring In An Animal, Jote T. Bulcha, Gabrielle E. Giese, Zulfikar Ali, Yong-Uk Lee, Melissa D. Walker, Amy D. Holdorf, L. Safak Yilmaz, Robert C. Brewster, Albertha J. M. Walhout

University of Massachusetts Medical School Faculty Publications

Persistence detection is a mechanism that ensures a physiological output is only executed when the relevant input is sustained. Gene regulatory network circuits known as coherent type 1 feed forward loops (FFLs) with an AND-logic gate have been proposed to generate persistence detection. In such circuits two transcription factors (TFs) are both required to activate target genes and one of the two TFs activates the other. While numerous FFLs have been identified, examples of actual persistence detectors have only been described for bacteria. Here, we discover a transcriptional persistence detector in Caenorhabditis elegans involving the nuclear hormone receptors nhr-10 and ...


The Cjun Nh2-Terminal Kinase (Jnk) Signaling Pathway Promotes Genome Stability And Prevents Tumor Initiation, Nomeda A. Girnius, Yvonne J. K. Edwards, David S. Garlick, Roger J. Davis Jun 2018

The Cjun Nh2-Terminal Kinase (Jnk) Signaling Pathway Promotes Genome Stability And Prevents Tumor Initiation, Nomeda A. Girnius, Yvonne J. K. Edwards, David S. Garlick, Roger J. Davis

University of Massachusetts Medical School Faculty Publications

Breast cancer is the most commonly diagnosed malignancy in women. Analysis of breast cancer genomic DNA indicates frequent loss-of-function mutations in components of the cJUN NH2-terminal kinase (JNK) signaling pathway. Since JNK signaling can promote cell proliferation by activating the AP1 transcription factor, this apparent association of reduced JNK signaling with tumor development was unexpected. We examined the effect of JNK deficiency in the murine breast epithelium. Loss of JNK signaling caused genomic instability and the development of breast cancer. Moreover, JNK deficiency caused widespread early neoplasia and rapid tumor formation in a murine model of breast cancer. This tumor ...


Aerobic Glycolysis Is Essential For Normal Rod Function And Controls Secondary Cone Death In Retinitis Pigmentosa, Lolita Petit, Shan Ma, Joris Cipi, Shun-Yun Cheng, Marina Zieger, Nissim Hay, Claudio Punzo May 2018

Aerobic Glycolysis Is Essential For Normal Rod Function And Controls Secondary Cone Death In Retinitis Pigmentosa, Lolita Petit, Shan Ma, Joris Cipi, Shun-Yun Cheng, Marina Zieger, Nissim Hay, Claudio Punzo

University of Massachusetts Medical School Faculty Publications

Aerobic glycolysis accounts for approximately 80%-90% of glucose used by adult photoreceptors (PRs); yet, the importance of aerobic glycolysis for PR function or survival remains unclear. Here, we further established the role of aerobic glycolysis in murine rod and cone PRs. We show that loss of hexokinase-2 (HK2), a key aerobic glycolysis enzyme, does not affect PR survival or structure but is required for normal rod function. Rods with HK2 loss increase their mitochondrial number, suggesting an adaptation to the inhibition of aerobic glycolysis. In contrast, cones adapt without increased mitochondrial number but require HK2 to adapt to metabolic ...


Syndromic Congenital Myelofibrosis Associated With A Loss-Of-Function Variant In Rbsn, Pilar L. Magoulas, Silvia Corvera, Luis M. Franco May 2018

Syndromic Congenital Myelofibrosis Associated With A Loss-Of-Function Variant In Rbsn, Pilar L. Magoulas, Silvia Corvera, Luis M. Franco

University of Massachusetts Medical School Faculty Publications

The human proteins rabenosyn-5 and VPS45 form a complex that plays a key role in early endocytosis. Pathogenic variants in VPS45 cause severe congenital neutropenia (SCN) with impaired neutrophil function, reticulin fibrosis of the bone marrow, and extramedullary hematopoiesis (OMIM: 615285). Patients with a specific VPS45 variant (p.Glu238Lys) also have intellectual disability and bilateral optic nerve hypoplasia. To date, the only evidence of a potential role for RBSN in human disease is the report of a homozygous missense variant (p.Gly425Arg) in a patient with intellectual disability, seizures, microcephaly, osteopenia, mild reticulin fibrosis of the bone marrow, and transient ...


Neuronal Modulation Of Brown Adipose Activity Through Perturbation Of White Adipocyte Lipogenesis, Adilson L. Guilherme, David J. Pedersen, Felipe Henriques, Alexander H. Bedard, Elizabeth Henchey, Mark Kelly, Kamal Rahmouni, Donald A. Morgan, Michael P. Czech May 2018

Neuronal Modulation Of Brown Adipose Activity Through Perturbation Of White Adipocyte Lipogenesis, Adilson L. Guilherme, David J. Pedersen, Felipe Henriques, Alexander H. Bedard, Elizabeth Henchey, Mark Kelly, Kamal Rahmouni, Donald A. Morgan, Michael P. Czech

University of Massachusetts Medical School Faculty Publications

White adipose tissue (WAT) secretes factors to communicate with other metabolic organs to maintain energy homeostasis. We previously reported that perturbation of adipocyte de novo lipogenesis (DNL) by deletion of fatty acid synthase (FASN) causes expansion of sympathetic neurons within white adipose tissue (WAT) and the appearance of beige adipocytes. Here we report evidence that white adipocyte DNL activity is also coupled to neuronal regulation and thermogenesis in brown adipose tissue (BAT). Induced deletion of FASN in all adipocytes in mature mice (iAdFASNKO) enhanced sympathetic innervation and neuronal activity as well as UCP1 expression in both WAT and BAT. In ...


Jip1-Mediated Jnk Activation Negatively Regulates Synaptic Plasticity And Spatial Memory, Caroline Morel, Tessi Sherrin, Norman J. Kennedy, Kelly H. Forest, Seda Barutcu, Michael Robles, Ezekiel Carpenter-Hyland, Naghum Alfulaij, Claire L. Standen, Robert A. Nichols, Morris Benveniste, Roger J. Davis, Cedomir Todorovic Apr 2018

Jip1-Mediated Jnk Activation Negatively Regulates Synaptic Plasticity And Spatial Memory, Caroline Morel, Tessi Sherrin, Norman J. Kennedy, Kelly H. Forest, Seda Barutcu, Michael Robles, Ezekiel Carpenter-Hyland, Naghum Alfulaij, Claire L. Standen, Robert A. Nichols, Morris Benveniste, Roger J. Davis, Cedomir Todorovic

University of Massachusetts Medical School Faculty Publications

The c-Jun N-terminal kinase (JNK) signal transduction pathway is implicated in learning and memory. Here, we examined the role of JNK activation mediated by the JIP1 scaffold protein. We compared male wild-type mice with a mouse model harboring a point mutation in the Jip1 gene that selectively blocks JIP1-mediated JNK activation. These male mutant mice exhibited increased NMDA receptor currents, increased NMDA receptor-mediated gene expression, and a lower threshold for induction of hippocampal long-term potentiation. The JIP1 mutant mice also displayed improved hippocampus-dependent spatial memory and enhanced associative fear conditioning. These results were confirmed using a second JIP1 mutant mouse ...


Effects Of Larval Density On Gene Regulation In Caenorhabditis Elegans During Routine L1 Synchronization, Io Long Chan, Oliver J. Rando, Colin C. Conine Mar 2018

Effects Of Larval Density On Gene Regulation In Caenorhabditis Elegans During Routine L1 Synchronization, Io Long Chan, Oliver J. Rando, Colin C. Conine

University of Massachusetts Medical School Faculty Publications

Bleaching gravid C. elegans followed by a short period of starvation of the L1 larvae is a routine method performed by worm researchers for generating synchronous populations for experiments. During the process of investigating dietary effects on gene regulation in L1 stage worms by single-worm RNA-Seq, we found that the density of resuspended L1 larvae affects expression of many mRNAs. Specifically, a number of genes related to metabolism and signalling are highly expressed in worms arrested at low density, but are repressed at higher arrest densities. We generated a GFP reporter strain based on one of the most density-dependent genes ...


Multiple Molecular Mechanisms Rescue Mtdna Disease In C. Elegans, Suraiya Haroon, Annie Li, Jaye L. Weinert, Clark Fritsch, Nolan G. Ericson, Jasmine Alexander-Floyd, Bart P. Braeckman, Cole M. Haynes, Jason H. Bielas, Tali Gidalevitz, Marc Vermulst Mar 2018

Multiple Molecular Mechanisms Rescue Mtdna Disease In C. Elegans, Suraiya Haroon, Annie Li, Jaye L. Weinert, Clark Fritsch, Nolan G. Ericson, Jasmine Alexander-Floyd, Bart P. Braeckman, Cole M. Haynes, Jason H. Bielas, Tali Gidalevitz, Marc Vermulst

University of Massachusetts Medical School Faculty Publications

Genetic instability of the mitochondrial genome (mtDNA) plays an important role in human aging and disease. Thus far, it has proven difficult to develop successful treatment strategies for diseases that are caused by mtDNA instability. To address this issue, we developed a model of mtDNA disease in the nematode C. elegans, an animal model that can rapidly be screened for genes and biological pathways that reduce mitochondrial pathology. These worms recapitulate all the major hallmarks of mtDNA disease in humans, including increased mtDNA instability, loss of respiration, reduced neuromuscular function, and a shortened lifespan. We found that these phenotypes could ...


The Cjun Nh2-Terminal Kinase (Jnk) Pathway Contributes To Mouse Mammary Gland Remodeling During Involution, Nomeda A. Girnius, Yvonne J. K. Edwards, Roger J. Davis Mar 2018

The Cjun Nh2-Terminal Kinase (Jnk) Pathway Contributes To Mouse Mammary Gland Remodeling During Involution, Nomeda A. Girnius, Yvonne J. K. Edwards, Roger J. Davis

University of Massachusetts Medical School Faculty Publications

Involution returns the lactating mammary gland to a quiescent state after weaning. The mechanism of involution involves collapse of the mammary epithelial cell compartment. To test whether the cJUN NH2-terminal kinase (JNK) signal transduction pathway contributes to involution, we established mice with JNK deficiency in the mammary epithelium. We found that JNK is required for efficient involution. JNK deficiency did not alter the STAT3/5 or SMAD2/3 signaling pathways that have been previously implicated in this process. Nevertheless, JNK promotes the expression of genes that drive involution, including matrix metalloproteases, cathepsins, and BH3-only proteins. These data demonstrate that JNK ...


Distinct Adipocyte Progenitor Cells Are Associated With Regional Phenotypes Of Perivascular Aortic Fat In Mice, Khanh-Van T. Tran, Timothy P. Fitzgibbons, So Yun Min, Tiffany Desouza, Silvia Corvera Mar 2018

Distinct Adipocyte Progenitor Cells Are Associated With Regional Phenotypes Of Perivascular Aortic Fat In Mice, Khanh-Van T. Tran, Timothy P. Fitzgibbons, So Yun Min, Tiffany Desouza, Silvia Corvera

University of Massachusetts Medical School Faculty Publications

OBJECTIVE: Perivascular adipose tissue depots around the aorta are regionally distinct and have specific functional properties. Thoracic aorta perivascular adipose tissue (tPVAT) expresses higher levels of thermogenic genes and lower levels of inflammatory genes than abdominal aorta perivascular adipose tissue (aPVAT). It is not known whether this distinction is due to the in-vivo functional environment or to cell-autonomous traits that persist outside the in-vivo setting. In this study, we asked whether the progenitor cells in tPVAT and aPVAT have cell-autonomous traits that lead to formation of regionally distinct PVAT.

METHODS: We performed microarray analysis of thoracic and abdominal peri-aortic adipose ...


Upr(Mt) Regulation And Output: A Stress Response Mediated By Mitochondrial-Nuclear Communication, Andrew Melber, Cole M. Haynes Feb 2018

Upr(Mt) Regulation And Output: A Stress Response Mediated By Mitochondrial-Nuclear Communication, Andrew Melber, Cole M. Haynes

University of Massachusetts Medical School Faculty Publications

The mitochondrial network is not only required for the production of energy, essential cofactors and amino acids, but also serves as a signaling hub for innate immune and apoptotic pathways. Multiple mechanisms have evolved to identify and combat mitochondrial dysfunction to maintain the health of the organism. One such pathway is the mitochondrial unfolded protein response (UPR(mt)), which is regulated by the mitochondrial import efficiency of the transcription factor ATFS-1 in C. elegans and potentially orthologous transcription factors in mammals (ATF4, ATF5, CHOP). Upon mitochondrial dysfunction, import of ATFS-1 into mitochondria is reduced, allowing it to be trafficked to ...


Rlim-Dependent And -Independent Pathways For X Chromosome Inactivation In Female Escs, Feng Wang, Kurtis N. Mccannell, Ana Boskovic, Xiaochun Zhu, Jongdae Shin, Jun Yu, Judith Gallant, Meg Byron, Jeanne B. Lawrence, Lihua Julie Zhu, Stephen N. Jones, Oliver J. Rando, Thomas G. Fazzio, Ingolf Bach Dec 2017

Rlim-Dependent And -Independent Pathways For X Chromosome Inactivation In Female Escs, Feng Wang, Kurtis N. Mccannell, Ana Boskovic, Xiaochun Zhu, Jongdae Shin, Jun Yu, Judith Gallant, Meg Byron, Jeanne B. Lawrence, Lihua Julie Zhu, Stephen N. Jones, Oliver J. Rando, Thomas G. Fazzio, Ingolf Bach

University of Massachusetts Medical School Faculty Publications

During female mouse embryogenesis, two forms of X chromosome inactivation (XCI) ensure dosage compensation from sex chromosomes. Beginning at the four-cell stage, imprinted XCI (iXCI) exclusively silences the paternal X (Xp), and this pattern is maintained in extraembryonic cell types. Epiblast cells, which give rise to the embryo proper, reactivate the Xp (XCR) and undergo a random form of XCI (rXCI) around implantation. Both iXCI and rXCI depend on the long non-coding RNA Xist. The ubiquitin ligase RLIM is required for iXCI in vivo and occupies a central role in current models of rXCI. Here, we demonstrate the existence of ...


Serine-Dependent Sphingolipid Synthesis Is A Metabolic Liability Of Aneuploid Cells, Sunyoung Hwang, H. Tobias Gustafsson, Ciara O'Sullivan, Gianna Bisceglia, Xinhe Huang, Christian Klose, Andrej Schevchenko, Robert C. Dickson, Paola Cavaliere, Noah Dephoure, Eduardo M. Torres Dec 2017

Serine-Dependent Sphingolipid Synthesis Is A Metabolic Liability Of Aneuploid Cells, Sunyoung Hwang, H. Tobias Gustafsson, Ciara O'Sullivan, Gianna Bisceglia, Xinhe Huang, Christian Klose, Andrej Schevchenko, Robert C. Dickson, Paola Cavaliere, Noah Dephoure, Eduardo M. Torres

University of Massachusetts Medical School Faculty Publications

Aneuploidy disrupts cellular homeostasis. However, the molecular mechanisms underlying the physiological responses and adaptation to aneuploidy are not well understood. Deciphering these mechanisms is important because aneuploidy is associated with diseases, including intellectual disability and cancer. Although tumors and mammalian aneuploid cells, including several cancer cell lines, show altered levels of sphingolipids, the role of sphingolipids in aneuploidy remains unknown. Here, we show that ceramides and long-chain bases, sphingolipid molecules that slow proliferation and promote survival, are increased by aneuploidy. Sphingolipid levels are tightly linked to serine synthesis, and inhibiting either serine or sphingolipid synthesis can specifically impair the fitness ...


Loss Of The Cone-Enriched Caspase-7 Does Not Affect Secondary Cone Death In Retinitis Pigmentosa, Aditya Venkatesh, Shun-Yun Cheng, Claudio Punzo Dec 2017

Loss Of The Cone-Enriched Caspase-7 Does Not Affect Secondary Cone Death In Retinitis Pigmentosa, Aditya Venkatesh, Shun-Yun Cheng, Claudio Punzo

University of Massachusetts Medical School Faculty Publications

Purpose: The apoptotic mechanisms responsible for secondary cone death in retinitis pigmentosa (RP) remain largely unknown. The cone-enriched apoptotic protease caspase-7 (Casp7) is thought to be triggered by endoplasmic reticulum (ER) stress and plays a pivotal role in mice deficient in the cone cyclic nucleotide-gated channels, a deficiency that causes achromatopsia in humans and in mice with autosomal dominant rhodopsin mutations, in particular the T17M mutation. Thus, we tested in two mouse models of RP whether the cone-enriched Casp7 plays a role during secondary cone death.

Methods: Casp7 knockout mice were crossed to two different RP mouse models with significantly ...


Hepatic Dysfunction Caused By Consumption Of A High-Fat Diet, Anthony R. Soltis, Norman J. Kennedy, Xiaofeng Xin, Feng Zhou, Scott B. Ficarro, Yoon Sing Yap, Bryan J. Matthews, Douglas A. Lauffenburger, Forest M. White, Jarrod A. Marto, Roger J. Davis, Ernest Fraenkel Dec 2017

Hepatic Dysfunction Caused By Consumption Of A High-Fat Diet, Anthony R. Soltis, Norman J. Kennedy, Xiaofeng Xin, Feng Zhou, Scott B. Ficarro, Yoon Sing Yap, Bryan J. Matthews, Douglas A. Lauffenburger, Forest M. White, Jarrod A. Marto, Roger J. Davis, Ernest Fraenkel

University of Massachusetts Medical School Faculty Publications

Obesity is a major human health crisis that promotes insulin resistance and, ultimately, type 2 diabetes. The molecular mechanisms that mediate this response occur across many highly complex biological regulatory levels that are incompletely understood. Here, we present a comprehensive molecular systems biology study of hepatic responses to high-fat feeding in mice. We interrogated diet-induced epigenomic, transcriptomic, proteomic, and metabolomic alterations using high-throughput omic methods and used a network modeling approach to integrate these diverse molecular signals. Our model indicated that disruption of hepatic architecture and enhanced hepatocyte apoptosis are among the numerous biological processes that contribute to early liver ...


Crispr-Based Dna Imaging In Living Cells Reveals Cell Cycle-Dependent Chromosome Dynamics, Hanhui Ma, Li-Chun Tu, University Of Central Florida, Yu-Chieh Chung, David Grünwald, Shaojie Zhang, Thoru Pederson Sep 2017

Crispr-Based Dna Imaging In Living Cells Reveals Cell Cycle-Dependent Chromosome Dynamics, Hanhui Ma, Li-Chun Tu, University Of Central Florida, Yu-Chieh Chung, David Grünwald, Shaojie Zhang, Thoru Pederson

University of Massachusetts Medical School Faculty Publications

In contrast to the well-studied condensation and folding of chromosomes during mitosis, their dynamics in interphase are less understood. We developed a sensitive, multicolor system, CRISPR-Sirius, allowing the real-time tracking of the dynamics of chromosomal loci. We tracked loci kilobases to megabases apart and found significant variation in the inter-locus distances of each pair, indicating differing degrees of DNA contortion. We resolved two distinct modes of dynamics of loci: saltatory local movements as well as translational movements of the domain. The magnitude of both of these modes of movements increased from early to late G1, whereas the translational movements were ...


Alcohol-Related Changes In The Intestinal Microbiome Influence Neutrophil Infiltration, Inflammation And Steatosis In Early Alcoholic Hepatitis In Mice, Patrick Lowe, Benedek Gyongyosi, Abhishek Satishchandran, Arvin Iracheta-Vellve, Aditya Ambade, Karen Kodys, Donna Catalano, Doyle V. Ward, Gyongyi Szabo Mar 2017

Alcohol-Related Changes In The Intestinal Microbiome Influence Neutrophil Infiltration, Inflammation And Steatosis In Early Alcoholic Hepatitis In Mice, Patrick Lowe, Benedek Gyongyosi, Abhishek Satishchandran, Arvin Iracheta-Vellve, Aditya Ambade, Karen Kodys, Donna Catalano, Doyle V. Ward, Gyongyi Szabo

University of Massachusetts Medical School Faculty Publications

BACKGROUND: Alcohol-induced intestinal dysbiosis disrupts homeostatic gut-liver axis function and is essential in the development of alcoholic liver disease. Here, we investigate changes in enteric microbiome composition in a model of early alcoholic steatohepatitis and dissect the pathogenic role of intestinal microbes in alcohol-induced liver pathology.

MATERIALS AND METHODS: Wild type mice received a 10-day diet that was either 5% alcohol-containing or an isocaloric control diet plus a single binge. 16S rDNA sequencing defined the bacterial communities in the cecum of alcohol- and pair-fed animals. Some mice were treated with an antibiotic cocktail prior to and throughout alcohol feeding. Liver ...


Size-Dependent Expression Of The Mitotic Activator Cdc25 As A Mechanism Of Size Control In Fission Yeast, Daniel L. Keifenheim, Xi-Ming Sun, Edridge D'Souza, Makoto J. Ohira, Mira Magner, Lawrence Livermore National Laboratory, Samuel Marguerat, Nicholas R. Rhind Feb 2017

Size-Dependent Expression Of The Mitotic Activator Cdc25 As A Mechanism Of Size Control In Fission Yeast, Daniel L. Keifenheim, Xi-Ming Sun, Edridge D'Souza, Makoto J. Ohira, Mira Magner, Lawrence Livermore National Laboratory, Samuel Marguerat, Nicholas R. Rhind

University of Massachusetts Medical School Faculty Publications

Proper cell size is essential for cellular function (Hall et al., 2004). Nonetheless, despite more than 100 years of work on the subject, the mechanisms that maintain cell size homeostasis are largely mysterious (Marshall et al., 2012). Cells in growing populations maintain cell size within a narrow range by coordinating growth and division. Bacterial and eukaryotic cells both demonstrate homeostatic size control, which maintains population-level variation in cell size within a certain range, and returns the population average to that range if it is perturbed (Marshall et al., 2012; Turner et al., 2012; Amodeo and Skotheim, 2015). Recent work has ...


Intraflagellar Transport Protein Ift20 Is Essential For Male Fertility And Spermiogenesis In Mice, Zhengang Zhang, Wei Li, Yong Zhang, Ling Zhang, Maria E. Teves, Hong Liu, Jerome F. Strauss 3rd, Gregory J. Pazour, James A. Foster, Rex A. Hess, Zhibing Zhang Nov 2016

Intraflagellar Transport Protein Ift20 Is Essential For Male Fertility And Spermiogenesis In Mice, Zhengang Zhang, Wei Li, Yong Zhang, Ling Zhang, Maria E. Teves, Hong Liu, Jerome F. Strauss 3rd, Gregory J. Pazour, James A. Foster, Rex A. Hess, Zhibing Zhang

University of Massachusetts Medical School Faculty Publications

Intraflagellar transport (IFT) is a conserved mechanism thought to be essential for the assembly and maintenance of cilia and flagella. However, little is known about its role in mammalian sperm flagella formation. To fill this gap, we disrupted the Ift20 gene in male germ cells. Homozygous mutant mice were infertile with significantly reduced sperm counts and motility. In addition, abnormally shaped elongating spermatid heads and bulbous round spermatids were found in the lumen of the seminiferous tubules. Electron microscopy revealed increased cytoplasmic vesicles, fiber-like structures, abnormal accumulation of mitochondria and a decrease in mature lysosomes. The few developed sperm had ...


Altered Interleukin-10 Signaling In Skeletal Muscle Regulates Obesity-Mediated Inflammation And Insulin Resistance, Sezin Dagdeviren, Dae Young Jung, Eunjung Lee, Randall H. Friedline, Hye Lim Noh, Jong Hun. Kim, Payal R. Patel, Nicholas Tsitsilianos, Andrew V. Tsitsilianos, Duy A. Tran, George H. Tsougranis, Caitlyn C. Kearns, Cecilia P. Uong, Jung Yeon. Kwon, Werner Muller, Ki Won. Lee, Jason K. Kim Nov 2016

Altered Interleukin-10 Signaling In Skeletal Muscle Regulates Obesity-Mediated Inflammation And Insulin Resistance, Sezin Dagdeviren, Dae Young Jung, Eunjung Lee, Randall H. Friedline, Hye Lim Noh, Jong Hun. Kim, Payal R. Patel, Nicholas Tsitsilianos, Andrew V. Tsitsilianos, Duy A. Tran, George H. Tsougranis, Caitlyn C. Kearns, Cecilia P. Uong, Jung Yeon. Kwon, Werner Muller, Ki Won. Lee, Jason K. Kim

University of Massachusetts Medical School Faculty Publications

Skeletal muscle insulin resistance is a major characteristic of obesity and type 2 diabetes. Although obesity-mediated inflammation is causally associated with insulin resistance, the underlying mechanism is unclear. Here, we examined the effects of chronic obesity in mice with muscle-specific overexpression of interleukin-10 (MIL10). After 16 weeks of a high-fat diet (HFD), MIL10 mice became markedly obese but showed improved insulin action compared to that of wild-type mice, which was largely due to increased glucose metabolism and reduced inflammation in skeletal muscle. Since leptin regulates inflammation, the beneficial effects of interleukin-10 (IL-10) were further examined in leptin-deficient ob/ob mice ...


Chrebp Regulates Fructose-Induced Glucose Production Independently Of Insulin Signaling, Mi-Sung Kim, Sarah A. Krawczyk, Ludivine Doridot, Alan J. Fowler, Jennifer X. Wang, Sunia A. Trauger, Hye Lim Noh, Hee Joon Kang, John K. Meissen, Matthew Blatnik, Jason K. Kim, Michelle Lai, Mark A. Herman Nov 2016

Chrebp Regulates Fructose-Induced Glucose Production Independently Of Insulin Signaling, Mi-Sung Kim, Sarah A. Krawczyk, Ludivine Doridot, Alan J. Fowler, Jennifer X. Wang, Sunia A. Trauger, Hye Lim Noh, Hee Joon Kang, John K. Meissen, Matthew Blatnik, Jason K. Kim, Michelle Lai, Mark A. Herman

University of Massachusetts Medical School Faculty Publications

Obese, insulin-resistant states are characterized by a paradoxical pathogenic condition in which the liver appears to be selectively insulin resistant. Specifically, insulin fails to suppress glucose production, yet successfully stimulates de novo lipogenesis. The mechanisms underlying this dysregulation remain controversial. Here, we hypothesized that carbohydrate-responsive element-binding protein (ChREBP), a transcriptional activator of glycolytic and lipogenic genes, plays a central role in this paradox. Administration of fructose increased hepatic hexose-phosphate levels, activated ChREBP, and caused glucose intolerance, hyperinsulinemia, hypertriglyceridemia, and hepatic steatosis in mice. Activation of ChREBP was required for the increased expression of glycolytic and lipogenic genes as well as ...


An Alternative Splicing Program Promotes Adipose Tissue Thermogenesis, Santiago Vernia, Yvonne J. K. Edwards, Myoung Souk Han, Julie Cavanagh-Kyros, Tamera Barrett, Jason K. Kim, Roger J. Davis Sep 2016

An Alternative Splicing Program Promotes Adipose Tissue Thermogenesis, Santiago Vernia, Yvonne J. K. Edwards, Myoung Souk Han, Julie Cavanagh-Kyros, Tamera Barrett, Jason K. Kim, Roger J. Davis

University of Massachusetts Medical School Faculty Publications

Alternative pre-mRNA splicing expands the complexity of the transcriptome and controls isoform-specific gene expression. Whether alternative splicing contributes to metabolic regulation is largely unknown. Here we investigated the contribution of alternative splicing to the development of diet-induced obesity. We found that obesity-induced changes in adipocyte gene expression include alternative pre-mRNA splicing. Bioinformatics analysis associated part of this alternative splicing program with sequence specific NOVA splicing factors. This conclusion was confirmed by studies of mice with NOVA deficiency in adipocytes. Phenotypic analysis of the NOVA-deficient mice demonstrated increased adipose tissue thermogenesis and improved glycemia. We show that NOVA proteins mediate a ...


Endothelial Mitogen-Activated Protein Kinase Kinase Kinase Kinase 4 Is Critical For Lymphatic Vascular Development And Function, Rachel J. Roth Flach, Chang-An Guo, Laura V. Danai, Joseph C. Yawe, Sharvari Gujja, Yvonne J.K. Edwards, Michael P. Czech May 2016

Endothelial Mitogen-Activated Protein Kinase Kinase Kinase Kinase 4 Is Critical For Lymphatic Vascular Development And Function, Rachel J. Roth Flach, Chang-An Guo, Laura V. Danai, Joseph C. Yawe, Sharvari Gujja, Yvonne J.K. Edwards, Michael P. Czech

University of Massachusetts Medical School Faculty Publications

The molecular mechanisms underlying lymphatic vascular development and function are not well understood. Recent studies have suggested a role for endothelial cell (EC) mitogen-activated protein kinase kinase kinase kinase 4 (Map4k4) in developmental angiogenesis and atherosclerosis. Here, we show that constitutive loss of EC Map4k4 in mice causes postnatal lethality due to chylothorax, suggesting that Map4k4 is required for normal lymphatic vascular function. Mice constitutively lacking EC Map4k4 displayed dilated lymphatic capillaries, insufficient lymphatic valves, and impaired lymphatic flow; furthermore, primary ECs derived from these animals displayed enhanced proliferation compared with controls. Yeast 2-hybrid analyses identified the Ras GTPase-activating protein ...


Activation Of Mtorc1 Is Essential For Beta-Adrenergic Stimulation Of Adipose Browning, Dianxin Liu, Marica Bordicchia, Chaoying Zhang, Huafeng Fang, Wan Wei, Jian-Liang Li, Adilson L. Guilherme, Kalyani V. P. Guntur, Michael P. Czech, Sheila Collins May 2016

Activation Of Mtorc1 Is Essential For Beta-Adrenergic Stimulation Of Adipose Browning, Dianxin Liu, Marica Bordicchia, Chaoying Zhang, Huafeng Fang, Wan Wei, Jian-Liang Li, Adilson L. Guilherme, Kalyani V. P. Guntur, Michael P. Czech, Sheila Collins

University of Massachusetts Medical School Faculty Publications

A classic metabolic concept posits that insulin promotes energy storage and adipose expansion, while catecholamines stimulate release of adipose energy stores by hydrolysis of triglycerides through beta-adrenergic receptor (betaARs) and protein kinase A (PKA) signaling. Here, we have shown that a key hub in the insulin signaling pathway, activation of p70 ribosomal S6 kinase (S6K1) through mTORC1, is also triggered by PKA activation in both mouse and human adipocytes. Mice with mTORC1 impairment, either through adipocyte-specific deletion of Raptor or pharmacologic rapamycin treatment, were refractory to the well-known betaAR-dependent increase of uncoupling protein UCP1 expression and expansion of beige/brite ...


Pi3-Kinase Mutation Linked To Insulin And Growth Factor Resistance In Vivo, Jonathon N. Winnay, Marie H. Solheim, Ercument Dirice, Masaji Sakaguchi, Hye Lim Noh, Hee Joon Kang, Hirokazu Takahashi, Kishan K. Chudasama, Jason K. Kim, Anders Molven, C. Ronald Kahn, Pal R. Njolstad Apr 2016

Pi3-Kinase Mutation Linked To Insulin And Growth Factor Resistance In Vivo, Jonathon N. Winnay, Marie H. Solheim, Ercument Dirice, Masaji Sakaguchi, Hye Lim Noh, Hee Joon Kang, Hirokazu Takahashi, Kishan K. Chudasama, Jason K. Kim, Anders Molven, C. Ronald Kahn, Pal R. Njolstad

University of Massachusetts Medical School Faculty Publications

The phosphatidylinositol 3-kinase (PI3K) signaling pathway is central to the action of insulin and many growth factors. Heterozygous mutations in the gene encoding the p85alpha regulatory subunit of PI3K (PIK3R1) have been identified in patients with SHORT syndrome - a disorder characterized by short stature, partial lipodystrophy, and insulin resistance. Here, we evaluated whether SHORT syndrome-associated PIK3R1 mutations account for the pathophysiology that underlies the abnormalities by generating knockin mice that are heterozygous for the Pik3r1Arg649Trp mutation, which is homologous to the mutation found in the majority of affected individuals. Similar to the patients, mutant mice exhibited a reduction in body ...