140 results on '"Lemieux, Madeleine"'
Search Results
102. BET Bromodomain Inhibition as a Therapeutic Strategy to Target c-Myc
- Author
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Delmore, Jake E., primary, Issa, Ghayas C., additional, Lemieux, Madeleine E., additional, Rahl, Peter B., additional, Shi, Junwei, additional, Jacobs, Hannah M., additional, Kastritis, Efstathios, additional, Gilpatrick, Timothy, additional, Paranal, Ronald M., additional, Qi, Jun, additional, Chesi, Marta, additional, Schinzel, Anna C., additional, McKeown, Michael R., additional, Heffernan, Timothy P., additional, Vakoc, Christopher R., additional, Bergsagel, P. Leif, additional, Ghobrial, Irene M., additional, Richardson, Paul G., additional, Young, Richard A., additional, Hahn, William C., additional, Anderson, Kenneth C., additional, Kung, Andrew L., additional, Bradner, James E., additional, and Mitsiades, Constantine S., additional
- Published
- 2011
- Full Text
- View/download PDF
103. Inactivation of a Single Copy of Crebbp Selectively Alters Pre-mRNA Processing in Mouse Hematopoietic Stem Cells
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Lemieux, Madeleine E., primary, Cheng, Ziming, additional, Zhou, Qing, additional, White, Ruth, additional, Cornell, John, additional, Kung, Andrew L., additional, and Rebel, Vivienne I., additional
- Published
- 2011
- Full Text
- View/download PDF
104. Abstract 2575: Differentiation of NUT midline carcinoma by epigenomic reprogramming
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Schwartz, Brian, primary, Hofer, Matthias, additional, Lemieux, Madeleine, additional, Bauer, Daniel, additional, Cameron, Michael, additional, West, Nathan, additional, Agoston, Elin, additional, Ince, Tan, additional, Christie, Amanda, additional, Aster, Jon, additional, Sallan, Stephen, additional, Kung, Andrew, additional, Bradner, James, additional, and French, Chris A., additional
- Published
- 2011
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- View/download PDF
105. Abstract LB-237: Epigenetic antagonism between Polycomb and SWI/SNF complexes duringoncogenic transformation
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Wilson, Boris G., primary, Wang, Xi, additional, Shen, Xiaohua, additional, McKenna, Elizabeth S., additional, Lemieux, Madeleine E., additional, Cho, Yoon-Jae, additional, Koelhoffer, Edward C., additional, Pomeroy, Scott L., additional, Orkin, Stuart H., additional, and Roberts, Charles W.M, additional
- Published
- 2011
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106. Differentiation of NUT Midline Carcinoma by Epigenomic Reprogramming
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Schwartz, Brian E., primary, Hofer, Matthias D., additional, Lemieux, Madeleine E., additional, Bauer, Daniel E., additional, Cameron, Michael J., additional, West, Nathan H., additional, Agoston, Elin S., additional, Reynoird, Nicolas, additional, Khochbin, Saadi, additional, Ince, Tan A., additional, Christie, Amanda, additional, Janeway, Katherine A., additional, Vargas, Sara O., additional, Perez-Atayde, Antonio R., additional, Aster, Jon C., additional, Sallan, Stephen E., additional, Kung, Andrew L., additional, Bradner, James E., additional, and French, Christopher A., additional
- Published
- 2011
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- View/download PDF
107. Epigenetic Antagonism between Polycomb and SWI/SNF Complexes during Oncogenic Transformation
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Wilson, Boris G., primary, Wang, Xi, additional, Shen, Xiaohua, additional, McKenna, Elizabeth S., additional, Lemieux, Madeleine E., additional, Cho, Yoon-Jae, additional, Koellhoffer, Edward C., additional, Pomeroy, Scott L., additional, Orkin, Stuart H., additional, and Roberts, Charles W.M., additional
- Published
- 2011
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108. Abstract 2391: Hsp90-Dependent Regulation of HIF and angiogenic potential in clear-cell renal cell carcinoma
- Author
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Bohonowych, Jessica E., primary, Peng, Shuping, additional, Lemieux, Madeleine, additional, Kung, Andrew, additional, Lundgren, Karen, additional, and Isaacs, Jennifer, additional
- Published
- 2010
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- View/download PDF
109. Glioblastoma Inhibition by Cell Surface Immunoglobulin Protein EWI-2, In Vitro and In Vivo
- Author
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Kolesnikova, Tatiana V., primary, Kazarov, Alexander R., additional, Lemieux, Madeleine E., additional, Lafleur, Marc A., additional, Kesari, Santosh, additional, Kung, Andrew L., additional, and Hemler, Martin E., additional
- Published
- 2009
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- View/download PDF
110. Global Increase in H3K79 Dimethylation in Murine and Human MLL-AF4 Lymphoblastic Leukemias.
- Author
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Krivtsov, Andrei V., primary, Feng, Zhaohui, additional, Lemieux, Madeleine, additional, Faber, Joerg, additional, Xia, Xiaobo, additional, Kung, Andrew L., additional, and Armstrong, Scott A., additional
- Published
- 2007
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111. Correction: Sirt1 Regulates Insulin Secretion by Repressing UCP2 in Pancreatic ß Cells
- Author
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Bordone, Laura, primary, Motta, Maria Carla, additional, Picard, Frederic, additional, Robinson, Ashley, additional, Jhala, Ulupi S, additional, Apfeld, Javier, additional, McDonagh, Thomas, additional, Lemieux, Madeleine, additional, McBurney, Michael, additional, Szilvasi, Akos, additional, Easlon, Erin J, additional, Lin, Su-Ju, additional, and Guarente, Leonard, additional
- Published
- 2006
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112. Sirt1 Regulates Insulin Secretion by Repressing UCP2 in Pancreatic β Cells
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Bordone, Laura, primary, Motta, Maria Carla, additional, Picard, Frederic, additional, Robinson, Ashley, additional, Jhala, Ulupi S, additional, Apfeld, Javier, additional, McDonagh, Thomas, additional, Lemieux, Madeleine, additional, McBurney, Michael, additional, Szilvasi, Akos, additional, Easlon, Erin J, additional, Lin, Su-Ju, additional, and Guarente, Leonard, additional
- Published
- 2005
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113. La médiation et le règlement des conflits dans les services essentiels au Québec
- Author
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Lemieux, Madeleine, primary
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- 2005
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114. Mediator Kinase Phosphorylation of STAT1 S727 Promotes Growth of Neoplasms With JAK-STAT Activation
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Nitulescu, Ioana I., Meyer, Sara C., Wen, Qiang Jeremy, Crispino, John D., Lemieux, Madeleine E., Levine, Ross L., Pelish, Henry E., and Shair, Matthew D.
- Subjects
STAT1 ,MPN ,CDK8 ,Kinase inhibitor ,Leukemia ,Super-enhancer ,Cortistatin A ,Ruxolitinib - Abstract
Constitutive JAK-STAT signaling drives the proliferation of most myeloproliferative neoplasms (MPN) and a subset of acute myeloid leukemia (AML), but persistence emerges with chronic exposure to JAK inhibitors. MPN and post-MPN AML are dependent on tyrosine phosphorylation of STATs, but the role of serine STAT1 phosphorylation remains unclear. We previously demonstrated that Mediator kinase inhibitor cortistatin A (CA) reduced proliferation of JAK2-mutant AML in vitro and in vivo and also suppressed CDK8-dependent phosphorylation of STAT1 at serine 727. Here we report that phosphorylation of STAT1 S727 promotes the proliferation of AML cells with JAK-STAT pathway activation. Inhibition of serine phosphorylation by CA promotes growth arrest and differentiation, inhibits colony formation in MPN patient samples and reduces allele burden in MPN mouse models. These results reveal that STAT1 pS727 regulates growth and differentiation in JAK-STAT activated neoplasms and suggest that Mediator kinase inhibition represents a therapeutic strategy to regulate JAK-STAT signaling.
- Published
- 2017
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115. The Mammalian SIR2α Protein Has a Role in Embryogenesis and Gametogenesis
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McBurney, Michael W., primary, Yang, Xiaofeng, additional, Jardine, Karen, additional, Hixon, Mary, additional, Boekelheide, Kim, additional, Webb, John R., additional, Lansdorp, Peter M., additional, and Lemieux, Madeleine, additional
- Published
- 2003
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116. The transcription factor BATF operates as an essential differentiation checkpoint in early effector CD8+ T cells.
- Author
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Kurachi, Makoto, Barnitz, R Anthony, Yosef, Nir, Odorizzi, Pamela M, DiIorio, Michael A, Lemieux, Madeleine E, Yates, Kathleen, Godec, Jernej, Klatt, Martin G, Regev, Aviv, Wherry, E John, and Haining, W Nicholas
- Subjects
LEUCINE zippers ,CD80 antigen ,T cell differentiation ,INTERLEUKIN-17 ,GENE expression ,T cell receptors ,INFLAMMATION - Abstract
The transcription factor BATF is required for the differentiation of interleukin 17 (IL-17)-producing helper T cells (T
H 17 cells) and follicular helper T cells (TFH cells). Here we identified a fundamental role for BATF in regulating the differentiation of effector of CD8+ T cells. BATF-deficient CD8+ T cells showed profound defects in effector population expansion and underwent proliferative and metabolic catastrophe early after encountering antigen. BATF, together with the transcription factors IRF4 and Jun proteins, bound to and promoted early expression of genes encoding lineage-specific transcription-factors (T-bet and Blimp-1) and cytokine receptors while paradoxically repressing genes encoding effector molecules (IFN-γ and granzyme B). Thus, BATF amplifies T cell antigen receptor (TCR)-dependent expression of transcription factors and augments the propagation of inflammatory signals but restrains the expression of genes encoding effector molecules. This checkpoint prevents irreversible commitment to an effector fate until a critical threshold of downstream transcriptional activity has been achieved. [ABSTRACT FROM AUTHOR]- Published
- 2014
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117. Developmental Effects of Ectopic Expression of the Glucocorticoid Receptor DNA Binding Domain Are Alleviated by an Amino Acid Substitution That Interferes with Homeodomain Binding
- Author
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Wang, Jun Ming, primary, Préfontaine, Gratien G., additional, Lemieux, Madeleine E., additional, Pope, Louise, additional, Akimenko, Marie-Andrée, additional, and Haché, Robert J. G., additional
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- 1999
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118. Selective Binding of Steroid Hormone Receptors to Octamer Transcription Factors Determines Transcriptional Synergism at the Mouse Mammary Tumor Virus Promoter
- Author
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Préfontaine, Gratien G., primary, Walther, Rhian, additional, Giffin, Ward, additional, Lemieux, Madeleine E., additional, Pope, Louise, additional, and Haché, Robert J.G., additional
- Published
- 1999
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119. Recruitment of Octamer Transcription Factors to DNA by Glucocorticoid Receptor
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Préfontaine, Gratien G., primary, Lemieux, Madeleine E., additional, Giffin, Ward, additional, Schild-Poulter, Caroline, additional, Pope, Louise, additional, LaCasse, Eric, additional, Walker, Peter, additional, and Haché, Robert J. G., additional
- Published
- 1998
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120. Semantic Structures and Diagnostic Thinking of Experts and Novices
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Steward, David, primary, BORDAGE, GEORGES, additional, and LEMIEUX, MADELEINE, additional
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- 1991
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121. Integrative analysis of HIF binding and transactivation reveals its role in maintaining histone methylation homeostasis.
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Xiaobo Xia, Lemieux, Madeleine E., Wei Li, Carroll, Jason S., Brown, Myles, X. Shirley Liu, and Andrew L. Kung
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HYPOXEMIA , *TRANSCRIPTION factors , *GENE expression , *GENE targeting , *PROTEIN binding , *HISTONE deacetylase , *PHYSIOLOGICAL control systems , *EPIGENESIS , *GENETICS - Abstract
Adaptation to hypoxia is mediated through a coordinated transcriptional response driven largely by hypoxia-inducible factor 1 (HIF-1). We used ChIP-chip and gene expression profiling to identify direct targets of HIF-1 transactivation on a genome-wide scale. Several hundred direct HIF-1 targets were identified and, as expected, were highly enriched for proteins that facilitate metabolic adaptation to hypoxia. Surprisingly, there was also striking enrichment for the family of 2-oxoglutarate dioxygenases, including the jumonji-domain histone demethylases. We demonstrate that these histone demethylases are direct HIF targets, and their up-regulation helps maintain epigenetic homeostasis under hypoxic conditions. These results suggest that the coordinated increase in expression of several oxygendependent enzymes by HIF may help compensate for decreased levels of oxygen under conditions of cellular hypoxia. [ABSTRACT FROM AUTHOR]
- Published
- 2009
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122. Sirt1 Regulates Insulin Secretion by Repressing UCP2 in Pancreatic β Cells.
- Author
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Bordone, Laura, Motta, Maria Carla, Picard, Frederic, Robinson, Ashley, Jhala, Ulupi S., Apfeld, Javier, McDonagh, Thomas, Lemieux, Madeleine, McBurney, Michael, Szilvasi, Akos, Easlon, Erin J., Su-Ju Lin, and Guarente, Leonard
- Subjects
INSULIN ,SOMATOMEDIN ,CAENORHABDITIS elegans ,CAENORHABDITIS ,PANCREATIC secretions ,GLUCOSE ,BIOCHEMISTRY - Abstract
Sir2 and insulin/IGF-1 are the major pathways that impinge upon aging in lower organisms. In Caenorhabditis elegans a possible genetic link between Sir2 and the insulin/IGF-1 pathway has been reported. Here we investigate such a link in mammals. We show that Sirt1 positively regulates insulin secretion in pancreatic β cells. Sirt1 represses the uncoupling protein (UCP) gene UCP2 by binding directly to the UCP2 promoter. In β cell lines in which Sirt1 is reduced by SiRNA, UCP2 levels are elevated and insulin secretion is blunted. The up-regulation of UCP2 is associated with a failure of cells to increase ATP levels after glucose stimulation. Knockdown of UCP2 restores the ability to secrete insulin in cells with reduced Sirt1, showing that UCP2 causes the defect in glucose-stimulated insulin secretion. Food deprivation induces UCP2 in mouse pancreas, which may occur via a reduction in NAD (a derivative of niacin) levels in the pancreas and down-regulation of Sirt1. Sirt1 knockout mice display constitutively high UCP2 expression. Our findings show that Sirt1 regulates UCP2 in β cells to affect insulin secretion. [ABSTRACT FROM AUTHOR]
- Published
- 2006
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123. Recruitment of Octamer Transcription Factors to DNA by Glucocorticoid Receptor
- Author
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Pre´fontaine, Gratien G., Lemieux, Madeleine E., Giffin, Ward, Schild-Poulter, Caroline, Pope, Louise, LaCasse, Eric, Walker, Peter, and Hache´, Robert J. G.
- Abstract
ABSTRACTGlucocorticoid receptor (GR) and octamer transcription factors 1 and 2 (Oct-1/2) interact synergistically to activate the transcription of mouse mammary tumor virus and many cellular genes. Synergism correlates with cooperative DNA binding of the two factors in vitro. To examine the molecular basis for these cooperative interactions, we have studied the consequences of protein-protein binding between GR and Oct-1/2. We have determined that GR binds in solution to the octamer factor POU domain. Binding is mediated through an interface in the GR DNA binding domain that includes amino acids C500 and L501. In transfected mammalian cells, a transcriptionally inert wild-type but not an L501P GR peptide potentiated transcriptional activation by Oct-2 100-fold above the level that could be attained in the cell by expressing Oct-2 alone. Transcriptional activation correlated closely with a striking increase in the occupancy of octamer motifs adjacent to glucocorticoid response elements (GREs) on transiently transfected DNAs. Intriguingly, GR–Oct-1/2 binding was interrupted by the binding of GR to a GRE. We propose a model for transcriptional cooperativity in which GR–Oct-1/2 binding promotes an increase in the local concentration of octamer factors over glucocorticoid-responsive regulatory regions. These results reveal transcriptional cooperativity through a direct protein interaction between two sequence-specific transcription factors that is mediated in a way that is expected to restrict transcriptional effects to regulatory regions with DNA binding sites for both factors.
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- 1998
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124. Substrate stiffness modulates cardiac fibroblast activation, senescence, and proinflammatory secretory phenotypeSubstrate stiffness modulates cardiac fibroblast activation, senescence, and proinflammatory secretory phenotype.
- Author
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Felisbino, Marina B., Rubino, Marcello, Travers, Joshua G., Schuetze, Katherine B., Lemieux, Madeleine E., Anseth, Kristi S., Aguado, Brian A., and McKinsey, Timothy A.
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FIBROBLASTS , *HEART cells , *ETHYLENE glycol , *HEART fibrosis , *PHENOTYPES - Abstract
In vitro cultures of primary cardiac fibroblasts (CFs), the major extracellular matrix (ECM)-producing cells of the heart, are used to determine molecular mechanisms of cardiac fibrosis. However, the supraphysiologic stiffness of tissue culture polystyrene (TCPS) triggers the conversion of CFs into an activated myofibroblast-like state, and serial passage of the cells results in the induction of replicative senescence. These phenotypic switches confound the interpretation of experimental data obtained with cultured CFs. In an attempt to circumvent TCPS-induced activation and senescence of CFs, we used poly(ethylene glycol) (PEG) hydrogels as cell culture platforms with low and high stiffness formulations to mimic healthy and fibrotic hearts, respectively. Low hydrogel stiffness converted activated CFs into a quiescent state with a reduced abundance of a-smooth muscle actin (a-SMA)-containing stress fibers. Unexpectedly, lower substrate stiffness concomitantly augmented CF senescence, marked by elevated senescence-associated b-galactosidase (SA-b-Gal) activity and increased expression of p16 and p21, which are antiproliferative markers of senescence. Using dynamically stiffening hydrogels with phototunable cross-linking capabilities, we demonstrate that premature, substrate-induced CF senescence is partially reversible. RNA-sequencing analysis revealed widespread transcriptional reprogramming of CFs cultured on low-stiffness hydrogels, with a reduction in the expression of profibrotic genes encoding ECM proteins, and an attendant increase in expression of NF-κB-responsive inflammatory genes that typify the senescence-associated secretory phenotype (SASP). Our findings demonstrate that alterations in matrix stiffness profoundly impact CF cell state transitions, and suggest mechanisms by which CFs change phenotype in vivo depending on the stiffness of the myocardial microenvironment in which they reside. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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125. Constitutive Activation of Ras and Inactivation of Ink4a/ArfAllele Induce a Fully Penetrant B-Cell Acute Lymphoblastic Leukemia Phenotype in Mice
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Sewastianik, Tomasz, Jiang, Meng, Sukhdeo, Kumar, Patel, Sanjay, Kang, Yue, Alduaij, Ahmad, Dennis, Peter S., Xiong, Jessie, Pinkus, Geraldine S., Rich, Jeremy N., Lemieux, Madeleine E., Sharpless, Norman E., and Carrasco, Ruben D.
- Abstract
Despite recent advances in treatment, precursor-B-cell acute lymphoblastic leukemia (B-ALL) remains a challenging clinical entity. Recent genome-wide studies have uncovered frequent genetic alterations involving activating RAS pathway mutations and loss of the INK4A/ARFlocus suggesting their important role in the pathogenesis, relapse, and chemoresistance of B-ALL. Therefore, to better understand the oncogenic mechanisms by which these alterations might promote B-ALL and to develop an in vivopreclinical model of relapsed B-ALL, we engineered mouse strains with induced somatic KrasG12Dpathway activation and/or loss of Ink4a/Arfduring early stages of B-cell development.
- Published
- 2017
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126. BET bromodomain inhibition suppresses innate inflammatory and profibrotic transcriptional networks in heart failure
- Author
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Duan, Qiming, McMahon, Sarah, Anand, Priti, Shah, Hirsh, Thomas, Sean, Salunga, Hazel T., Huang, Yu, Zhang, Rongli, Sahadevan, Aarathi, Lemieux, Madeleine E., Brown, Jonathan D., Srivastava, Deepak, Bradner, James E., McKinsey, Timothy A., and Haldar, Saptarsi M.
- Abstract
BET bromodomain inhibition treats heart failure by blocking innate inflammatory and profibrotic gene networks.
- Published
- 2017
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127. The Transcription Factor BATF Controls CD8+T Cell Effector Differentiation
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Barnitz, R. Anthony, Kurachi, Makoto, Lemieux, Madeleine E., Yosef, Nir, DiIorio, Michael A., Yates, Kathleen B., Godec, Jernej, Odorizzi, Pamela, Regev, Aviv, Wherry, E. John, and Nicholas Haining, W.
- Abstract
Following activation by antigen, costimulation, and inflammation, naïve CD8+T cells initiate a program of clonal expansion and differentiation resulting in wide-spread changes in expression of genes involved in cell-cycle, metabolism, effector function, apoptosis, and homing. Although, several key transcription factors (TFs) have been shown to be important in effector CD8+T cell differentiation, the precise transcriptional regulation of this differentiation program remains poorly understood. The AP-1 family member BATF plays an important role in regulating differentiation and function in CD4+Th17 cells, CD4+follicular helper T cells, and in Ig class switching in B cells. We now show that BATF is also required for effector CD8+T cell differentiation and regulates a core program of genes involved in effector differentiation. We found that BATF expression is rapidly up-regulated during effector CD8+T cell differentiation in the mouse model of lymphocytic choriomeningitis virus (LCMV) infection. To examine the role of BATF in effector differentiation, we studied congenically distinct wild type (WT) and BATF knockout (KO) naïve P14 TCR transgenic CD8+T cells co- transferred into a WT host. Upon infection, the BATF KO cells exhibited a profound, cell-intrinsic defect in effector CD8+T cell differentiation, with a ∼400-fold decrease in peak number of effector cells. BATF KO effectors showed sustained activation and increased cell death by the mid-expansion phase of the immune response. To address the question of how loss of BATF causes such a severely diminished antigen-specific response, we profiled the binding sites of BATF throughout the genome by chromatin immunoprecipitation and high-throughput sequencing (ChIP-seq) in primary CD8+effector cells. We found that BATF bound to regulatory regions in many genes critical for effector differentiation, including transcription factors (e.g. Tbx21, Eomes, Prdm1), genes involved in cytokine signaling (e.g. Il12rb2, Il2ra), homing (e.g. Sell, Selp, Ccr9), effector function (e.g. Gzmb, Ifng, Il2), apoptosis (e.g. Bcl2, Bcl2l1, Mcl1), and T cell activation (e.g. Ctla4, Cd247, Tnfrsf4), suggesting a major role for BATF in effector CD8+T cell differentiation. Indeed, we found that genes bound by BATF were highly significantly overrepresented among genes that changed as a result of naïve CD8+T cells differentiating into effectors in vivo(P = 10-27). Comparison of gene expression in in vitroWT and BATF KO effectors confirmed that BATF bound genes were perturbed by BATF loss of function. Analysis of the kinetics of gene expression during the first 72 hours of effector differentiation showed that loss of BATF perturbed the temporal sequence of expression of critical transcription factors, such as T-bet and Eomes, and resulted in inappropriately early cytokine expression. This suggests that BATF may be required to coordinate the earliest events in CD8+T cell effector differentiation. To test this hypothesis, we used in vivoCFSE tracking to follow the early CD8+T cell response during LCMV infection. We found that while BATF KO CD8+T cells initiate cell division, there was a dramatic collapse in the ability to sustain proliferation and differentiation as early as day 3 post-infection. These results indicate that BATF ensures the orderly progression of a program of genes required by effector cells, restraining the expression of some and promoting the expression of others. More broadly, our results suggest that BATF may provide a common regulatory infrastructure for the development of effector cells in all T cell lineages.
- Published
- 2013
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128. Matrix-Degrading Enzyme Expression and Aortic Fibrosis During Continuous-Flow Left Ventricular Mechanical Support.
- Author
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Ambardekar, Amrut V., Stratton, Matthew S., Dobrinskikh, Evgenia, Hunter, Kendall S., Tatman, Philip D., Lemieux, Madeleine E., Cleveland, Joseph C., Tuder, Rubin M., Weiser-Evans, Mary C.M., Moulton, Karen S., and McKinsey, Timothy A.
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AORTA , *HEART assist devices , *GENE expression , *ARTIFICIAL blood circulation , *VASCULAR remodeling - Abstract
Background: The effects of nonphysiological flow generated by continuous-flow (CF) left ventricular assist devices (LVADs) on the aorta remain poorly understood.Objectives: The authors sought to quantify indexes of fibrosis and determine the molecular signature of post-CF-LVAD vascular remodeling.Methods: Paired aortic tissue was collected at CF-LVAD implant and subsequently at transplant from 22 patients. Aortic wall morphometry and fibrillar collagen content (a measure of fibrosis) was quantified. In addition, whole-transcriptome profiling by RNA sequencing and follow-up immunohistochemistry were performed to evaluate CF-LVAD-mediated changes in aortic mRNA and protein expression.Results: The mean age was 52 ± 12 years, with a mean duration of CF-LVAD of 224 ± 193 days (range 45-798 days). There was a significant increase in the thickness of the collagen-rich adventitial layer from 218 ± 110 μm pre-LVAD to 410 ± 209 μm post-LVAD (P < 0.01). Furthermore, there was an increase in intimal and medial mean fibrillar collagen intensity from 22 ± 11 a.u. pre-LVAD to 41 ± 24 a.u. post-LVAD (P < 0.0001). The magnitude of this increase in fibrosis was greater among patients with longer durations of CF-LVAD support. CF-LVAD led to profound down-regulation in expression of extracellular matrix-degrading enzymes, such as matrix metalloproteinase-19 and ADAMTS4, whereas no evidence of fibroblast activation was noted.Conclusions: There is aortic remodeling and fibrosis after CF-LVAD that correlates with the duration of support. This fibrosis is due, at least in part, to suppression of extracellular matrix-degrading enzyme expression. Further research is needed to examine the contribution of nonphysiological flow patterns on vascular function and whether modulation of pulsatility may improve vascular remodeling and long-term outcomes. [ABSTRACT FROM AUTHOR]- Published
- 2021
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129. Book reviews.
- Author
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Lemieux, Madeleine
- Subjects
- ADMINISTRATIVE Law in Canada (Book)
- Abstract
Reviews the book `Administrative Law in Canada,' by Sara Blake.
- Published
- 1995
130. Ectopic protein interactions within BRD4-chromatin complexes drive oncogenic megadomain formation in NUT midline carcinoma.
- Author
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Alekseyenko, Artyom A., Walsh, Erica M., Zee, Barry M., Pakozdi, Tibor, Hsi, Peter, Lemieux, Madeleine E., Cin, Paola Dal, Ince, Tan A., Kharchenko, Peter V., Kuroda, Mitzi I., and French, Christopher A.
- Subjects
- *
NUCLEAR protein genetics , *CARCINOMA , *MYC oncogenes , *TUMOR proteins , *PROTEIN domains - Abstract
To investigate the mechanism that drives dramatic mistargeting of active chromatin in NUT midline carcinoma (NMC), we have identified protein interactions unique to the BRD4-NUT fusion oncoprotein compared with wild-type BRD4. Using cross-linking, affinity purification, and mass spectrometry, we identified the EP300 acetyltransferase as uniquely associated with BRD4 through the NUT fusion in both NMC and non-NMC cell types. We also discovered ZNF532 associated with BRD4-NUT in NMC patient cells but not detectable in 293T cells. EP300 and ZNF532 are both implicated in feed-forward regulatory loops leading to propagation of the oncogenic chromatin complex in BRD4-NUT patient cells. Adding key functional significance to our biochemical findings, we independently discovered a ZNF532-NUT translocation fusion in a newly diagnosed NMC patient. ChIP sequencing of the major players NUT, ZNF532, BRD4, EP300, and H3K27ac revealed the formation of ZNF532-NUT-associated hyperacetylated megadomains, distinctly localized but otherwise analogous to those found in BRD4-NUT patient cells. Our results support a model in which NMC is dependent on ectopic NUT-mediated interactions between EP300 and components of BRD4 regulatory complexes, leading to a cascade of misregulation. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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131. Glucocorticoids enhance muscle endurance and ameliorate Duchenne muscular dystrophy through a defined metabolic program.
- Author
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Morrison-Nozik, Alexander, Anand, Priti, Han Zhu, Qiming Duan, Sabeh, Mohamad, Prosdocimo, Domenick A., Lemieux, Madeleine E., Nordsborg, Nikolai, Russell, Aaron P., MacRae, Calum A., Gerber, Anthony N., Jain, Mukesh K., and Haldar, Saptarsi M.
- Subjects
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GLUCOCORTICOIDS , *DUCHENNE muscular dystrophy , *ERGOGENIC aids , *SKELETAL muscle , *TRANSCRIPTION factors - Abstract
Classic physiology studies dating to the 1930s demonstrate that moderate or transient glucocorticoid (GC) exposure improves muscle performance. The ergogenic properties of GCs are further evidenced by their surreptitious use as doping agents by endurance athletes and poorly understood efficacy in Duchenne muscular dystrophy (DMD), a genetic muscle-wasting disease. A defined molecular basis underlying these performance-enhancing properties of GCs in skeletal muscle remains obscure. Here, we demonstrate that ergogenic effects of GCs are mediated by direct induction of the metabolic transcription factor KLF15, defining a downstream pathway distinct from that resulting in GC-related muscle atrophy. Furthermore, we establish that KLF15 deficiency exacerbates dystrophic severity and muscle GC-KLF15 signaling mediates salutary therapeutic effects in the mdx mouse model of DMD. Thus, although glucocorticoid receptor (GR)-mediated transactivation is often associated with muscle atrophy and other adverse effects of pharmacologic GC administration, our data define a distinct GR-induced gene regulatory pathway that contributes to therapeutic effects of GCs in DMD through proergogenic metabolic programming. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
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132. Stable inhibitory activity of regulatory T cells requires the transcription factor Helios.
- Author
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Hye-Jung Kim, Barnitz, R. Anthony, Kreslavsky, Taras, Brown, Flavian D., Moffett, Howell, Lemieux, Madeleine E., Kaygusuz, Yasemin, Meissner, Torsten, Holderried, Tobias A. W., Chan, Susan, Kastner, Philippe, Haining, W. Nicholas, and Cantor, Harvey
- Subjects
- *
T cells , *CELLULAR control mechanisms , *INHIBITION (Chemistry) , *GENE expression , *SCURFIN (Protein) , *GENETIC transcription , *FORKHEAD transcription factors , *GENETICS of autoimmune diseases , *CELLULAR immunity , *MICE genetics , *CHARTS, diagrams, etc. , *MAMMALS - Abstract
The maintenance of immune homeostasis requires regulatory T cells (Tregs). Given their intrinsic self-reactivity, Tregs must stably maintain a suppressive phenotype to avoid autoimmunity. We report that impaired expression of the transcription factor (TF) Helios by FoxP3+ CD4 and Qa-1-restricted CD8 Tregs results in defective regulatory activity and autoimmunity in mice. Helios-deficient Tregs develop an unstable phenotype during inflammatory responses characterized by reduced FoxP3 expression and increased effector cytokine expression secondary to diminished activation of the STAT5 pathway. CD8 Tregs also require Helios-dependent STAT5 activation for survival and to prevent terminal T cell differentiation. The definition of Helios as a key transcription factor that stabilizes Tregs in the face of inflammatory responses provides a genetic explanation for a core property of Tregs. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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133. EZH2 Cooperates with BRD4-NUT to Drive NUT Carcinoma Growth by Silencing Key Tumor Suppressor Genes.
- Author
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Huang Y, Durall RT, Luong NM, Hertzler HJ, Huang J, Gokhale PC, Leeper BA, Persky NS, Root DE, Anekal PV, Montero Llopis PDLM, David CN, Kutok JL, Raimondi A, Saluja K, Luo J, Zahnow CA, Adane B, Stegmaier K, Hawkins CE, Ponne C, Le Q, Shapiro GI, Lemieux ME, Eagen KP, and French CA
- Subjects
- Animals, Humans, Mice, Cell Cycle Proteins genetics, Cell Cycle Proteins metabolism, Cell Line, Tumor, Chromatin, Enhancer of Zeste Homolog 2 Protein genetics, Enhancer of Zeste Homolog 2 Protein metabolism, Genes, Tumor Suppressor, Histones metabolism, Neoplasm Recurrence, Local genetics, Transcription Factors genetics, Transcription Factors metabolism, Carcinoma genetics, Nuclear Proteins genetics, Nuclear Proteins metabolism
- Abstract
NUT carcinoma is an aggressive carcinoma driven by the BRD4-NUT fusion oncoprotein, which activates chromatin to promote expression of progrowth genes. BET bromodomain inhibitors (BETi) are a promising treatment for NUT carcinoma that can impede BRD4-NUT's ability to activate genes, but the efficacy of BETi as monotherapy is limited. Here, we demonstrated that enhancer of zeste homolog 2 (EZH2), which silences genes through establishment of repressive chromatin, is a dependency in NUT carcinoma. Inhibition of EZH2 with the clinical compound tazemetostat potently blocked growth of NUT carcinoma cells. Epigenetic and transcriptomic analysis revealed that tazemetostat reversed the EZH2-specific H3K27me3 silencing mark and restored expression of multiple tumor suppressor genes while having no effect on key oncogenic BRD4-NUT-regulated genes. Indeed, H3K27me3 and H3K27ac domains were found to be mutually exclusive in NUT carcinoma cells. CDKN2A was identified as the only gene among all tazemetostat-derepressed genes to confer resistance to tazemetostat in a CRISPR-Cas9 screen. Combined inhibition of EZH2 and BET synergized to downregulate cell proliferation genes, resulting in more pronounced growth arrest and differentiation than either inhibitor alone. In preclinical models, combined tazemetostat and BETi synergistically blocked tumor growth and prolonged survival of NUT carcinoma-xenografted mice, with complete remission without relapse in one cohort. Identification of EZH2 as a dependency in NUT carcinoma substantiates the reliance of NUT carcinoma tumor cells on epigenetic dysregulation of functionally opposite, yet highly complementary, chromatin regulatory pathways to maintain NUT carcinoma growth., Significance: Repression of tumor suppressor genes, including CDKN2A, by EZH2 provides a mechanistic rationale for combining EZH2 and BET inhibitors for the clinical treatment of NUT carcinoma. See related commentary by Kazansky and Kentsis, p. 3827., (©2023 American Association for Cancer Research.)
- Published
- 2023
- Full Text
- View/download PDF
134. Torsional and strain dysfunction precede overt heart failure in a mouse model of dilated cardiomyopathy pathogenesis.
- Author
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Holmes JB, Lemieux ME, and Stelzer JE
- Subjects
- Mice, Animals, Echocardiography methods, Ventricular Function, Left physiology, Stroke Volume physiology, Cardiomyopathy, Dilated etiology, Cardiomyopathy, Dilated genetics, Heart Failure etiology, Heart Failure genetics, Ventricular Dysfunction, Left etiology, Ventricular Dysfunction, Left genetics
- Abstract
Detailed assessments of whole heart mechanics are crucial for understanding the consequences of sarcomere perturbations that lead to cardiomyopathy in mice. Echocardiography offers an accessible and cost-effective method of obtaining metrics of cardiac function, but the most routine imaging and analysis protocols might not identify subtle mechanical deficiencies. This study aims to use advanced echocardiography imaging and analysis techniques to identify previously unappreciated mechanical deficiencies in a mouse model of dilated cardiomyopathy (DCM) before the onset of overt systolic heart failure (HF). Mice lacking muscle LIM protein expression (MLP
-/- ) were used to model DCM-linked HF pathogenesis. Left ventricular (LV) function of MLP-/- and wild-type (WT) controls were studied at 3, 6, and 10 wk of age using conventional and four-dimensional (4-D) echocardiography, followed by speckle-tracking analysis to assess torsional and strain mechanics. Mice were also studied with RNA-seq. Although 3-wk-old MLP-/- mice showed normal LV ejection fraction (LVEF), these mice displayed abnormal torsional and strain mechanics alongside reduced β-adrenergic reserve. Transcriptome analysis showed that these defects preceded most molecular markers of HF. However, these markers became upregulated as MLP-/- mice aged and developed overt systolic dysfunction. These findings indicate that subtle deficiencies in LV mechanics, undetected by LVEF and conventional molecular markers, may act as pathogenic stimuli in DCM-linked HF. Using these analyses in future studies will further help connect in vitro measurements of the sarcomere function to whole heart function. NEW & NOTEWORTHY A detailed study of how perturbations to sarcomere proteins impact whole heart mechanics in mouse models is a major yet challenging step in furthering our understanding of cardiovascular pathophysiology. This study uses advanced echocardiographic imaging and analysis techniques to reveal previously unappreciated subclinical whole heart mechanical defects in a mouse model of cardiomyopathy. In doing so, it offers an accessible set of measurements for future studies to use when connecting sarcomere and whole heart function.- Published
- 2023
- Full Text
- View/download PDF
135. EZH2 synergizes with BRD4-NUT to drive NUT carcinoma growth through silencing of key tumor suppressor genes.
- Author
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Huang Y, Durall RT, Luong NM, Hertzler HJ, Huang J, Gokhale PC, Leeper BA, Persky NS, Root DE, Anekal PV, Montero Llopis PDLM, David CN, Kutok JL, Raimondi A, Saluja K, Luo J, Zahnow CA, Adane B, Stegmaier K, Hawkins CE, Ponne C, Le Q, Shapiro GI, Lemieux ME, Eagen KP, and French CA
- Abstract
NUT carcinoma (NC) is an aggressive carcinoma driven by the BRD4-NUT fusion oncoprotein, which activates chromatin to promote expression of pro-growth genes. BET bromodomain inhibitors (BETi) impede BRD4-NUT's ability to activate genes and are thus a promising treatment but limited as monotherapy. The role of gene repression in NC is unknown. Here, we demonstrate that EZH2, which silences genes through establishment of repressive chromatin, is a dependency in NC. Inhibition of EZH2 with the clinical compound tazemetostat (taz) potently blocked growth of NC cells. Epigenetic and transcriptomic analysis revealed that taz reversed the EZH2-specific H3K27me3 silencing mark, and restored expression of multiple tumor suppressor genes while having no effect on key oncogenic BRD4- NUT-regulated genes. CDKN2A was identified as the only gene amongst all taz-derepressed genes to confer resistance to taz in a CRISPR-Cas9 screen. Combined EZH2 inhibition and BET inhibition synergized to downregulate cell proliferation genes resulting in more pronounced growth arrest and differentiation than either inhibitor alone. In pre-clinical models, combined taz and BETi synergistically blocked growth and prolonged survival of NC-xenografted mice, with all mice cured in one cohort., Statement of Significance: Identification of EZH2 as a dependency in NC substantiates the reliance of NC tumor cells on epigenetic dysregulation of functionally opposite, yet highly complementary chromatin regulatory pathways to maintain NC growth. In particular, repression of CDKN2A expression by EZH2 provides a mechanistic rationale for combining EZH2i with BETi for the clinical treatment of NC.
- Published
- 2023
- Full Text
- View/download PDF
136. Detection of early-stage lung cancer in sputum using automated flow cytometry and machine learning.
- Author
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Lemieux ME, Reveles XT, Rebeles J, Bederka LH, Araujo PR, Sanchez JR, Grayson M, Lai SC, DePalo LR, Habib SA, Hill DG, Lopez K, Patriquin L, Sussman R, Joyce RP, and Rebel VI
- Subjects
- Humans, Early Detection of Cancer methods, Flow Cytometry, Lung, Machine Learning, Sputum, Lung Neoplasms diagnostic imaging
- Abstract
Background: Low-dose spiral computed tomography (LDCT) may not lead to a clear treatment path when small to intermediate-sized lung nodules are identified. We have combined flow cytometry and machine learning to develop a sputum-based test (CyPath Lung) that can assist physicians in decision-making in such cases., Methods: Single cell suspensions prepared from induced sputum samples collected over three consecutive days were labeled with a viability dye to exclude dead cells, antibodies to distinguish cell types, and a porphyrin to label cancer-associated cells. The labeled cell suspension was run on a flow cytometer and the data collected. An analysis pipeline combining automated flow cytometry data processing with machine learning was developed to distinguish cancer from non-cancer samples from 150 patients at high risk of whom 28 had lung cancer. Flow data and patient features were evaluated to identify predictors of lung cancer. Random training and test sets were chosen to evaluate predictive variables iteratively until a robust model was identified. The final model was tested on a second, independent group of 32 samples, including six samples from patients diagnosed with lung cancer., Results: Automated analysis combined with machine learning resulted in a predictive model that achieved an area under the ROC curve (AUC) of 0.89 (95% CI 0.83-0.89). The sensitivity and specificity were 82% and 88%, respectively, and the negative and positive predictive values 96% and 61%, respectively. Importantly, the test was 92% sensitive and 87% specific in cases when nodules were < 20 mm (AUC of 0.94; 95% CI 0.89-0.99). Testing of the model on an independent second set of samples showed an AUC of 0.85 (95% CI 0.71-0.98) with an 83% sensitivity, 77% specificity, 95% negative predictive value and 45% positive predictive value. The model is robust to differences in sample processing and disease state., Conclusion: CyPath Lung correctly classifies samples as cancer or non-cancer with high accuracy, including from participants at different disease stages and with nodules < 20 mm in diameter. This test is intended for use after lung cancer screening to improve early-stage lung cancer diagnosis. Trial registration ClinicalTrials.gov ID: NCT03457415; March 7, 2018., (© 2023. The Author(s).)
- Published
- 2023
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137. A chromosome-level genome of Astyanax mexicanus surface fish for comparing population-specific genetic differences contributing to trait evolution.
- Author
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Warren WC, Boggs TE, Borowsky R, Carlson BM, Ferrufino E, Gross JB, Hillier L, Hu Z, Keene AC, Kenzior A, Kowalko JE, Tomlinson C, Kremitzki M, Lemieux ME, Graves-Lindsay T, McGaugh SE, Miller JT, Mommersteeg MTM, Moran RL, Peuß R, Rice ES, Riddle MR, Sifuentes-Romero I, Stanhope BA, Tabin CJ, Thakur S, Yamamoto Y, and Rohner N
- Subjects
- Animals, Biological Evolution, Caves, Chromosome Mapping, Evolution, Molecular, Gene Editing, Genome genetics, Homeodomain Proteins genetics, Mitogen-Activated Protein Kinase Phosphatases genetics, Quantitative Trait Loci genetics, Adaptation, Physiological genetics, Characidae embryology, Characidae genetics, Eye embryology, Multifactorial Inheritance genetics
- Abstract
Identifying the genetic factors that underlie complex traits is central to understanding the mechanistic underpinnings of evolution. Cave-dwelling Astyanax mexicanus populations are well adapted to subterranean life and many populations appear to have evolved troglomorphic traits independently, while the surface-dwelling populations can be used as a proxy for the ancestral form. Here we present a high-resolution, chromosome-level surface fish genome, enabling the first genome-wide comparison between surface fish and cavefish populations. Using this resource, we performed quantitative trait locus (QTL) mapping analyses and found new candidate genes for eye loss such as dusp26. We used CRISPR gene editing in A. mexicanus to confirm the essential role of a gene within an eye size QTL, rx3, in eye formation. We also generated the first genome-wide evaluation of deletion variability across cavefish populations to gain insight into this potential source of cave adaptation. The surface fish genome reference now provides a more complete resource for comparative, functional and genetic studies of drastic trait differences within a species.
- Published
- 2021
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138. BPTF regulates growth of adult and pediatric high-grade glioma through the MYC pathway.
- Author
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Green AL, DeSisto J, Flannery P, Lemma R, Knox A, Lemieux M, Sanford B, O'Rourke R, Ramkissoon S, Jones K, Perry J, Hui X, Moroze E, Balakrishnan I, O'Neill AF, Dunn K, DeRyckere D, Danis E, Safadi A, Gilani A, Hubbell-Engler B, Nuss Z, Levy JMM, Serkova N, Venkataraman S, Graham DK, Foreman N, Ligon K, Jones K, Kung AL, and Vibhakar R
- Abstract
High-grade gliomas (HGG) afflict both children and adults and respond poorly to current therapies. Epigenetic regulators have a role in gliomagenesis, but a broad, functional investigation of the impact and role of specific epigenetic targets has not been undertaken. Using a two-step, in vitro/in vivo epigenomic shRNA inhibition screen, we determine the chromatin remodeler BPTF to be a key regulator of adult HGG growth. We then demonstrate that BPTF knockdown decreases HGG growth in multiple pediatric HGG models as well. BPTF appears to regulate tumor growth through cell self-renewal maintenance, and BPTF knockdown leads these glial tumors toward more neuronal characteristics. BPTF's impact on growth is mediated through positive effects on expression of MYC and MYC pathway targets. HDAC inhibitors synergize with BPTF knockdown against HGG growth. BPTF inhibition is a promising strategy to combat HGG through epigenetic regulation of the MYC oncogenic pathway.
- Published
- 2020
- Full Text
- View/download PDF
139. Dynamic Chromatin Targeting of BRD4 Stimulates Cardiac Fibroblast Activation.
- Author
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Stratton MS, Bagchi RA, Felisbino MB, Hirsch RA, Smith HE, Riching AS, Enyart BY, Koch KA, Cavasin MA, Alexanian M, Song K, Qi J, Lemieux ME, Srivastava D, Lam MPY, Haldar SM, Lin CY, and McKinsey TA
- Subjects
- Animals, Azepines pharmacology, Azepines therapeutic use, Cell Adhesion Molecules genetics, Cell Adhesion Molecules metabolism, Cells, Cultured, Enhancer Elements, Genetic, Epigenesis, Genetic, Extracellular Matrix metabolism, Female, Fibrosis, Heart Failure drug therapy, Heart Failure genetics, Heart Ventricles cytology, Heart Ventricles metabolism, Heart Ventricles pathology, Intracellular Signaling Peptides and Proteins antagonists & inhibitors, Intracellular Signaling Peptides and Proteins genetics, Male, Mice, Mice, Inbred C57BL, Nuclear Proteins antagonists & inhibitors, Nuclear Proteins genetics, Protein Binding, RNA Polymerase II metabolism, Rats, Rats, Sprague-Dawley, Transcription Factors antagonists & inhibitors, Transcription Factors genetics, Transcriptome, Transforming Growth Factor beta genetics, Transforming Growth Factor beta metabolism, Triazoles pharmacology, Triazoles therapeutic use, p38 Mitogen-Activated Protein Kinases metabolism, Chromatin metabolism, Heart Failure metabolism, Intracellular Signaling Peptides and Proteins metabolism, Myofibroblasts metabolism, Nuclear Proteins metabolism, Transcription Factors metabolism
- Abstract
Rationale: Small molecule inhibitors of the acetyl-histone binding protein BRD4 have been shown to block cardiac fibrosis in preclinical models of heart failure (HF). However, since the inhibitors target BRD4 ubiquitously, it is unclear whether this chromatin reader protein functions in cell type-specific manner to control pathological myocardial fibrosis. Furthermore, the molecular mechanisms by which BRD4 stimulates the transcriptional program for cardiac fibrosis remain unknown., Objective: We sought to test the hypothesis that BRD4 functions in a cell-autonomous and signal-responsive manner to control activation of cardiac fibroblasts, which are the major extracellular matrix-producing cells of the heart., Methods and Results: RNA-sequencing, mass spectrometry, and cell-based assays employing primary adult rat ventricular fibroblasts demonstrated that BRD4 functions as an effector of TGF-β (transforming growth factor-β) signaling to stimulate conversion of quiescent cardiac fibroblasts into Periostin ( Postn )-positive cells that express high levels of extracellular matrix. These findings were confirmed in vivo through whole-transcriptome analysis of cardiac fibroblasts from mice subjected to transverse aortic constriction and treated with the small molecule BRD4 inhibitor, JQ1. Chromatin immunoprecipitation-sequencing revealed that BRD4 undergoes stimulus-dependent, genome-wide redistribution in cardiac fibroblasts, becoming enriched on a subset of enhancers and super-enhancers, and leading to RNA polymerase II activation and expression of downstream target genes. Employing the Sertad4 (SERTA domain-containing protein 4) locus as a prototype, we demonstrate that dynamic chromatin targeting of BRD4 is controlled, in part, by p38 MAPK (mitogen-activated protein kinase) and provide evidence of a critical function for Sertad4 in TGF-β-mediated cardiac fibroblast activation., Conclusions: These findings define BRD4 as a central regulator of the pro-fibrotic cardiac fibroblast phenotype, establish a p38-dependent signaling circuit for epigenetic reprogramming in heart failure, and uncover a novel role for Sertad4 . The work provides a mechanistic foundation for the development of BRD4 inhibitors as targeted anti-fibrotic therapies for the heart.
- Published
- 2019
- Full Text
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140. The absence of SIR2alpha protein has no effect on global gene silencing in mouse embryonic stem cells.
- Author
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McBurney MW, Yang X, Jardine K, Bieman M, Th'ng J, and Lemieux M
- Subjects
- Acetylation, Animals, DNA Repair physiology, Gene Expression Regulation, Neoplastic, Histones metabolism, Mice, Proviruses genetics, Retroviridae genetics, Retroviridae Infections genetics, Sirtuin 1, Stem Cells cytology, Stem Cells radiation effects, Tumor Cells, Cultured, Tumor Suppressor Protein p53 metabolism, X-Rays, Carcinoma, Embryonal, Gene Silencing physiology, Sirtuins genetics, Sirtuins metabolism, Stem Cells physiology
- Abstract
The yeast sir2 gene plays a central role in mediating gene silencing and DNA repair in this organism. The mouse sir2alpha gene is closely related to its yeast homologue and encodes a nuclear protein expressed at particularly high levels in embryonic stem (ES) cells. We used homologous recombination to create ES cells null for sir2alpha and found that these cells did not have elevated levels of acetylated histones and did not ectopically express silent genes. Unlike yeast sir2 mutants, our sir2alpha null ES cells had normal sensitivity to insults such as ionizing radiation and heat shock, and they were able to silence invading retroviruses normally. These sir2alpha null cells were able to differentiate in culture normally. Our results failed to provide evidence that the mammalian SIR2alpha protein plays a role in gene silencing and suggest that the physiological substrate(s) for the SIR2alpha deacetylase may be nuclear proteins other than histones.
- Published
- 2003
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