DOCSLIB.ORG

FHL2 Inhibits Calcineurin and Represses Pathological Cardiac

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
FHL2 Inhibits Calcineurin and Represses Pathological Cardiac FHL2 INHIBITS CALCINEURIN AND REPRESSES PATHOLOGICAL CARDIAC HYPERTROPHY APPROVED BY SUPERVISORY COMMITTEE Joseph A. Hill, M.D., Ph.D. (Mentor) Joseph A. Garcia, M.D., Ph.D. (Committee Chair) Michael A. White, Ph.D. Keith A. Wharton, M.D., Ph.D. DEDICATION To Dr. Joseph A. Hill who has for many years been a mentor, a role model, and a friend. What impressed me the most is his passion and enthusiasm for cardiovascular research, his hard work running the division of cardiology and still keep up with everyone’s project in the laboratory. From him I learned not only how to design experiments, but also how to present the findings, and critically address the literature as well as my own data. He was always there to support me when I needed support. Thank you, Joe, I’ve learned a lot from you. To Dr. Beverly A. Rothermel and her open-door policy. Bev was very influential in my training and education over these years. This work would not have been possible without her contribution, suggestions and troubleshooting. To Dr. Thomas Gillette for his discussions and expertise inside and outside the laboratory. Tom helped me to wrap up the project by pinpointing the crucial experiments to strengthen my work and put it on paper. To my high school biology teacher, Rejep Tanish, who recognized my interest in biology and set in motion the trajectory which took me from Turkmenistan, to Turkey, to United States of America. To my parents, Akmele and Hajymammet, who gave me freedom and support to pursue my interest in biological sciences abroad, even though it meant leaving them for a long time. Their love and belief in me gave me strength throughout my education. Finally, to my beautiful wife, Jennet, for her love and support. She left her comfortable life and family to come to USA with me. She gave me a beautiful baby boy, Eziz, who was my motivation during writing of my thesis. FHL2 INHIBITS CALCINEURIN AND REPRESSES PATHOLOGICAL CARDIAC HYPERTROPHY by BERDYMAMMET HOJAYEV DISSERTATION Presented to the Faculty of the Graduate School of Biomedical Sciences The University of Texas Southwestern Medical Center at Dallas In Partial Fulfillment of the Requirements For the Degree of DOCTOR OF PHILOSOPHY The University of Texas Southwestern Medical Center at Dallas Dallas, Texas June, 2010 Copyright by BERDYMAMMET HOJAYEV, 2010 All Rights Reserved FHL2 INHIBITS CALCINEURIN AND REPRESSES PATHOLOGICAL CARDIAC HYPERTROPHY BERDYMAMMET HOJAYEV, Ph.D. The University of Texas Southwestern Medical Center at Dallas, 2010 JOSEPH A. HILL, M.D., Ph.D. Stress-induced cardiac hypertrophy is a hallmark feature of pathological remodeling which, left unchecked, predisposes hearts to arrhythmia and failure. FHL2 is a member of the four-and-a-half LIM domain (FHL) family of proteins expressed predominantly in the heart. Targeted disruption of FHL2 leads to an exaggerated response to beta-agonist (isoproterenol)-induced cardiac hypertrophy. Isoproterenol-induced hypertrophy relies on activation of the calcineurin-NFAT pathway, and inhibition of calcineurin is sufficient to block growth in response to isoproterenol. I also observed that FHL2 is up-regulated in mouse hearts after isoproterenol treatment. Based on this, we hypothesized that FHL2 negatively v regulates the calcineurin-NFAT pathway and consequently, the hypertrophic growth response. To determine whether calcineurin signaling is enhanced in the absence of FHL2, wild type (WT) and FHL2 knockout (FHL2-/-) mice were treated with isoproterenol (32 mg/kg/day). We observed a significant increase in isoproterenol-induced expression of the NFAT target genes RCAN1.4 and BNP in FHL2-/- hearts as compared to WT. To determine whether the effect of FHL2 on the abundance of NFAT target gene transcripts was mediated by calcineurin- NFAT-dependent transcription, HEK 293 cells were transfected with luciferase reporter constructs containing the NFAT-driven promoters of either RCAN1 or IL-2. Consistent with the in vivo data, knockdown of FHL2 message using siRNA led to increases in both RCAN1 and IL-2 promoter activities elicited by constitutively active calcineurin or the calcium ionophore, ionomycin. Importantly, activation of the RCAN1 promoter by ionomycin, in control and FHL2 knockdown cells, was abolished by the calcineurin inhibitor cyclosporin A, confirming the calcineurin dependence of the response. Over-expression of FHL2 in HEK 293 cells inhibited the activation of both NFAT reporters triggered by either constitutively active calcineurin or ionomycin. Furthermore, neonatal rat ventricular myocytes over-expressing FHL2 exhibited reduced hypertrophic growth in response to constitutively active calcineurin (measured by cell cross- sectional area and fetal gene expression). Finally, immunostaining of adult cardiomyocytes revealed co-localization of FHL2 and calcineurin predominantly vi at the sarcomere, and activation of calcineurin by endothelin-1 treatment resulted in interaction between FHL2 and calcineurin as demonstrated by co- immunoprecipitation. These observations demonstrate that FHL2 represses calcineurin-NFAT signaling and thereby suppresses hypertrophic cardiac growth at least in part by interacting with calcineurin and inhibiting its activation. vii TABLE OF CONTENTS ABSTRACT ............................................................................................................v TABLE OF CONTENTS ..................................................................................... viii PRIOR PUBLICATIONS ........................................................................................x LIST OF FIGURES .............................................................................................. xi ABBREVIATIONS ............................................................................................. xii CHAPTER 1: INTRODUCTION • Heart failure – epidemiologic burden……………..………………………2 • Progression to heart failure………………………………………………..3 • Hypertrophy as therapeutic target………………………………………....4 • Calcineurin/NFAT pathway…………………………………………….…5 • FHL2……………………………………………………………………....8 o FHL2 expression pattern and regulation…………………………..9 o FHL2 and MEK/ERK pathway………………………………….10 o FHL2 and β-catenin……………………………………………...13 o FHL2 in cancer…………………………………………………..16 o FHL2 as transcription factor……………………………………..18 o FHL2 in the heart………………………………………………...19 • Central thesis……………………………………………………………..22 • References……………………………………………………………….23 CHAPTER 2: FHL2 INHIBITS CALCINEURIN AND REPRESSES PATHOLOGICAL CARDIAC HYPERTROPHY • Introduction…………………………………………………………….30 • Results o Differential roles of FHL2 in various models of hypertrophy….33 β-adrenergic agonist induced hypertrophy………………….33 Pressure overload-induced hypertrophy…………………….34 Constitutively active calcineurin-induced hypertrophy……..35 o Increased FHL2 expression in WT mice treated with isoproterenol……………………………………………………..36 o Activation NFAT target genes in FHL2-/- mouse hearts………..38 o Increased expression of NFAT target genes in FHL2-/- mice…..40 o Knockdown of FHL2 protein in vitro enhances calcineurin- dependent NFAT promoter activation…………………………...41 viii o FHL2 levels in vitro modulate activation of NFAT target genes by calcineurin……………………………………………………….43 o FHL2 inhibits calcineurin-dependent hypertrophic responses in neonatal rat ventricular myocytes……………………………….44 o FHL2 localizes to the sarcomere in adult and neonatal cardiomyocytes………………………………………………….45 o FHL2 co-localizes and interacts with calcineurin…………….....46 • Interpretation and Conclusion o Inhibition of hypertrophy by FHL2 in vivo……………………..49 o Inhibition of calcineurin/NFAT pathway by FHL2……………..51 o Localization to sarcomere……………………………………….53 o FHL2 interacts with calcineurin………………………………...54 • Figures…………………………………………………………………...55 • Material and Methods…………………………………………………..73 • References………………………………………………………………78 CHAPTER 3: DISCUSSION • Increased FHL2 expression after isoproterenol infusion……………….82 • Inhibition of calcineurin by FHL2………………………………………84 • FHL2 and the MEK1/1-ERK1/2 pathway……………………………..87 • Suppression of MEK1/2-ERK1/2 pathway through calcineurin………..89 • FHL2 and FHL1………………………………………………………..91 • FHL2 in TAC and isoproterenol-induced hypertrophy…………………92 • Regulation of binding of FHL2…………………………………………94 • Perspective………………………………………………………………96 • Figures…………………………………………………………………..97 • References….............................................................................................98 ix PRIOR PUBLICATIONS Matta H, Hojayev B, Tomar R, Chugh P, & Chaudhary PM (2003) Use of lentiviral vectors for delivery of small interfering RNA. Cancer Biol Ther 2(2):206-210 x LIST OF FIGURES Figure 2.1: Absence of FHL2 amplifies isoproterenol-induced cardiac hypertrophy ………………………………………………………55 Figure 2.2: Increased expression of FHL2 in hearts of isoproterenol-treated mouse hearts…………………………………………..…………..57 Figure 2.3: Increased expression of NFAT target genes in FHL2 knockout mice following isoproterenol stimulation………………………………59 Figure 2.4: Induction NFAT target gene BNP by constitutively active calcineurin in FHL2-/- hearts …………………………..………..60 Figure 2.5: Absence of FHL2 enhances NFAT target gene expression in mouse hearts collected in the morning………………………..………….61 Figure 2.6: Increased heart weight to body weight ratio in FHL2-/- mice at 1 year of age…………………………………………………….…..63 Figure 2.7: Knockdown of FHL2 augments NFAT-dependent expression by calcineurin…………………………………………………….…..64 Figure 2.8: FHL2 modulates NFAT-dependent promoter activity by calcineurin………………………………………………………...66
Load more

Recommended publications
  • RBP-J Signaling − Cells Through Notch Novel IRF8-Controlled
    Sca-1+Lin−CD117− Mesenchymal Stem/Stromal Cells Induce the Generation of Novel IRF8-Controlled Regulatory Dendritic Cells through Notch −RBP-J Signaling This information is current as of September 25, 2021. Xingxia Liu, Shaoda Ren, Chaozhuo Ge, Kai Cheng, Martin Zenke, Armand Keating and Robert C. H. Zhao J Immunol 2015; 194:4298-4308; Prepublished online 30 March 2015; doi: 10.4049/jimmunol.1402641 Downloaded from http://www.jimmunol.org/content/194/9/4298 Supplementary http://www.jimmunol.org/content/suppl/2015/03/28/jimmunol.140264 http://www.jimmunol.org/ Material 1.DCSupplemental References This article cites 59 articles, 19 of which you can access for free at: http://www.jimmunol.org/content/194/9/4298.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 25, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2015 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Sca-1+Lin2CD1172 Mesenchymal Stem/Stromal Cells Induce the Generation of Novel IRF8-Controlled Regulatory Dendritic Cells through Notch–RBP-J Signaling Xingxia Liu,*,1 Shaoda Ren,*,1 Chaozhuo Ge,* Kai Cheng,* Martin Zenke,† Armand Keating,‡,x and Robert C.
    [Show full text]
  • Single Cell Transcriptomics Reveal Temporal Dynamics of Critical Regulators of Germ Cell Fate During Mouse Sex Determination
    bioRxiv preprint doi: https://doi.org/10.1101/747279; this version posted November 2, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 Single cell transcriptomics reveal temporal dynamics of critical regulators of germ 2 cell fate during mouse sex determination 3 Authors: Chloé Mayère1,2, Yasmine Neirijnck1,3, Pauline Sararols1, Chris M Rands1, 4 Isabelle Stévant1,2, Françoise Kühne1, Anne-Amandine Chassot3, Marie-Christine 5 Chaboissier3, Emmanouil T. Dermitzakis1,2, Serge Nef1,2,*. 6 Affiliations: 7 1Department of Genetic Medicine and Development, University of Geneva, 1211 Geneva, 8 Switzerland; 9 2iGE3, Institute of Genetics and Genomics of Geneva, University of Geneva, 1211 10 Geneva, Switzerland; 11 3Université Côte d'Azur, CNRS, Inserm, iBV, France; 12 Lead Contact: 13 *Corresponding Author: Serge Nef, 1 rue Michel-Servet CH-1211 Genève 4, 14 [email protected]. + 41 (0)22 379 51 93 15 Running Title: Single cell transcriptomics of germ cells 1 bioRxiv preprint doi: https://doi.org/10.1101/747279; this version posted November 2, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 16 Abbreviations; 17 AGC: Adrenal Germ Cell 18 GC: Germ cell 19 OGC: Ovarian Germ Cell 20 TGC: Testicular Germ Cell 21 scRNA-seq: Single-cell RNA-Sequencing 22 DEG: Differentially Expressed Gene 23 24 25 Keywords: 26 Single-cell RNA-Sequencing (scRNA-seq), sex determination, ovary, testis, gonocytes, 27 oocytes, prospermatogonia, meiosis, gene regulatory network, germ cells, development, 28 RNA splicing 29 2 bioRxiv preprint doi: https://doi.org/10.1101/747279; this version posted November 2, 2020.
    [Show full text]
  • Olig2 and Ngn2 Function in Opposition to Modulate Gene Expression in Motor Neuron Progenitor Cells
    Downloaded from genesdev.cshlp.org on September 29, 2021 - Published by Cold Spring Harbor Laboratory Press Olig2 and Ngn2 function in opposition to modulate gene expression in motor neuron progenitor cells Soo-Kyung Lee,1 Bora Lee,1 Esmeralda C. Ruiz, and Samuel L. Pfaff2 Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA Spinal motor neurons and oligodendrocytes are generated sequentially from a common pool of progenitors termed pMN cells. Olig2 is a bHLH-class transcription factor in pMN cells, but it has remained unclear how its transcriptional activity is modulated to first produce motor neurons and then oligodendrocytes. Previous studies have shown that Olig2 primes pMN cells to become motor neurons by triggering the expression of Ngn2 and Lhx3. Here we show that Olig2 also antagonizes the premature expression of post-mitotic motor neuron genes in pMN cells. This blockade is counteracted by Ngn2, which accumulates heterogeneously in pMN cells, thereby releasing a subset of the progenitors to differentiate and activate expression of post-mitotic motor neuron genes. The antagonistic relationship between Ngn2 and Olig2 is mediated by protein interactions that squelch activity as well as competition for shared DNA-binding sites. Our data support a model in which the Olig2/Ngn2 ratio in progenitor cells serves as a gate for timing proper gene expression during the development of pMN cells: Olig2high maintains the pMN state, thereby holding cells in reserve for oligodendrocyte generation, whereas Ngn2high favors the conversion of pMN cells into post-mitotic motor neurons. [Keywords: Motor neuron; oligodendrocyte; development; basic helix–loop–helix (bHLH); neurogenin (Ngn); Olig] Supplemental material is available at http://www.genesdev.org.
    [Show full text]
  • Landscape of Transcriptional Deregulation in Lung Cancer Shu Zhang1,2,3,4, Mingfa Li1, Hongbin Ji2,3,4,5* and Zhaoyuan Fang2,3,4,6*
    Zhang et al. BMC Genomics (2018) 19:435 https://doi.org/10.1186/s12864-018-4828-1 RESEARCHARTICLE Open Access Landscape of transcriptional deregulation in lung cancer Shu Zhang1,2,3,4, Mingfa Li1, Hongbin Ji2,3,4,5* and Zhaoyuan Fang2,3,4,6* Abstract Background: Lung cancer is a very heterogeneous disease that can be pathologically classified into different subtypes including small-cell lung carcinoma (SCLC), lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC) and large-cell carcinoma (LCC). Although much progress has been made towards the oncogenic mechanism of each subtype, transcriptional circuits mediating the upstream signaling pathways and downstream functional consequences remain to be systematically studied. Results: Here we trained a one-class support vector machine (OC-SVM) model to establish a general transcription factor (TF) regulatory network containing 325 TFs and 18724 target genes. We then applied this network to lung cancer subtypes and identified those deregulated TFs and downstream targets. We found that the TP63/SOX2/ DMRT3 module was specific to LUSC, corresponding to squamous epithelial differentiation and/or survival. Moreover, the LEF1/MSC module was specifically activated in LUAD and likely to confer epithelial-to-mesenchymal transition, known important for cancer malignant progression and metastasis. The proneural factor, ASCL1, was specifically up-regulated in SCLC which is known to have a neuroendocrine phenotype. Also, ID2 was differentially regulated between SCLC and LUSC, with its up-regulation in SCLC linking to energy supply for fast mitosis and its down-regulation in LUSC linking to the attenuation of immune response. We further described the landscape of TF regulation among the three major subtypes of lung cancer, highlighting their functional commonalities and specificities.
    [Show full text]
  • The E–Id Protein Axis Modulates the Activities of the PI3K–AKT–Mtorc1
    Downloaded from genesdev.cshlp.org on October 6, 2021 - Published by Cold Spring Harbor Laboratory Press The E–Id protein axis modulates the activities of the PI3K–AKT–mTORC1– Hif1a and c-myc/p19Arf pathways to suppress innate variant TFH cell development, thymocyte expansion, and lymphomagenesis Masaki Miyazaki,1,8 Kazuko Miyazaki,1,8 Shuwen Chen,1 Vivek Chandra,1 Keisuke Wagatsuma,2 Yasutoshi Agata,2 Hans-Reimer Rodewald,3 Rintaro Saito,4 Aaron N. Chang,5 Nissi Varki,6 Hiroshi Kawamoto,7 and Cornelis Murre1 1Department of Molecular Biology, University of California at San Diego, La Jolla, California 92093, USA; 2Department of Biochemistry and Molecular Biology, Shiga University of Medical School, Shiga 520-2192, Japan; 3Division of Cellular Immunology, German Cancer Research Center, D-69120 Heidelberg, Germany; 4Department of Medicine, University of California at San Diego, La Jolla, California 92093, USA; 5Center for Computational Biology, Institute for Genomic Medicine, University of California at San Diego, La Jolla, California 92093, USA; 6Department of Pathology, University of California at San Diego, La Jolla, California 92093, USA; 7Department of Immunology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan It is now well established that the E and Id protein axis regulates multiple steps in lymphocyte development. However, it remains unknown how E and Id proteins mechanistically enforce and maintain the naı¨ve T-cell fate. Here we show that Id2 and Id3 suppressed the development and expansion of innate variant follicular helper T (TFH) cells. Innate variant TFH cells required major histocompatibility complex (MHC) class I-like signaling and were associated with germinal center B cells.
    [Show full text]
  • Active Estrogen Receptor-Alpha Signaling in Ovarian Cancer Models and Clinical Specimens
    Author Manuscript Published OnlineFirst on January 10, 2017; DOI: 10.1158/1078-0432.CCR-16-1501 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 Active estrogen receptor-alpha signaling in ovarian cancer models and clinical specimens Courtney L. Andersen1,2,3,12, Matthew J. Sikora1,3, Michelle M. Boisen3,4, Tianzhou Ma5, Alec Christie3, George Tseng5, Yongseok Park5, Soumya Luthra6, Uma Chandran6, Paul Haluska7, Gina M. Mantia- Smaldone8, Kunle Odunsi9, Karen McLean10, Adrian V. Lee1,3, Esther Elishaev11, Robert P. Edwards4, Steffi Oesterreich1,2,3 Affiliations: 1Department of Pharmacology & Chemical Biology, University of Pittsburgh; 2Molecular Pharmacology Training Program, University of Pittsburgh; 3Women’s Cancer Research Center, University of Pittsburgh Cancer Institute; 4Department of Obstetrics, Gynecology, & Reproductive Sciences, Magee- Womens Hospital of UPMC; 5Department of Biostatistics, University of Pittsburgh; 6Department of Biomedical Informatics, University of Pittsburgh; 7Oncology, Merck Research Laboratories; 8Department of Surgical Oncology, Fox Chase Cancer Center; 9Department of Gynecologic Oncology, Roswell Park Cancer Institute; 10Division of Gynecologic Oncology, University of Michigan; 11Department of Pathology, Magee- Womens Hospital of UPMC; 12Present address: IMED Oncology, AstraZeneca Corresponding Author: Steffi Oesterreich, PhD.: B411 Womens Cancer Research Center, University of Pittsburgh Cancer Institute, Magee-Womens Research Institute, 204 Craft
    [Show full text]
  • The Id-Protein Family in Developmental and Cancer-Associated Pathways Cornelia Roschger and Chiara Cabrele*
    Roschger and Cabrele Cell Communication and Signaling (2017) 15:7 DOI 10.1186/s12964-016-0161-y REVIEW Open Access The Id-protein family in developmental and cancer-associated pathways Cornelia Roschger and Chiara Cabrele* Abstract Inhibitors of DNA binding and cell differentiation (Id) proteins are members of the large family of the helix-loop- helix (HLH) transcription factors, but they lack any DNA-binding motif. During development, the Id proteins play a key role in the regulation of cell-cycle progression and cell differentiation by modulating different cell-cycle regulators both by direct and indirect mechanisms. Several Id-protein interacting partners have been identified thus far, which belong to structurally and functionally unrelated families, including, among others, the class I and II bHLH transcription factors, the retinoblastoma protein and related pocket proteins, the paired-box transcription factors, and the S5a subunit of the 26 S proteasome. Although the HLH domain of the Id proteins is involved in most of their protein-protein interaction events, additional motifs located in their N-terminal and C-terminal regions are required for the recognition of diverse protein partners. The ability of the Id proteins to interact with structurally different proteins is likely to arise from their conformational flexibility: indeed, these proteins contain intrinsically disordered regions that, in the case of the HLH region, undergo folding upon self- or heteroassociation. Besides their crucial role for cell-fate determination and cell-cycle progression during development, other important cellular events have been related to the Id-protein expression in a number of pathologies. Dysregulated Id-protein expression has been associated with tumor growth, vascularization, invasiveness, metastasis, chemoresistance and stemness, as well as with various developmental defects and diseases.
    [Show full text]
  • At the X-Roads of Sex and Genetics in Pulmonary Arterial Hypertension
    G C A T T A C G G C A T genes Review At the X-Roads of Sex and Genetics in Pulmonary Arterial Hypertension Meghan M. Cirulis 1,2,* , Mark W. Dodson 1,2, Lynn M. Brown 1,2, Samuel M. Brown 1,2, Tim Lahm 3,4,5 and Greg Elliott 1,2 1 Division of Pulmonary, Critical Care and Occupational Medicine, University of Utah, Salt Lake City, UT 84132, USA; [email protected] (M.W.D.); [email protected] (L.M.B.); [email protected] (S.M.B.); [email protected] (G.E.) 2 Division of Pulmonary and Critical Care Medicine, Intermountain Medical Center, Salt Lake City, UT 84107, USA 3 Division of Pulmonary, Critical Care, Sleep and Occupational Medicine, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; [email protected] 4 Richard L. Roudebush Veterans Affairs Medical Center, Indianapolis, IN 46202, USA 5 Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA * Correspondence: [email protected]; Tel.: +1-801-581-7806 Received: 29 September 2020; Accepted: 17 November 2020; Published: 20 November 2020 Abstract: Group 1 pulmonary hypertension (pulmonary arterial hypertension; PAH) is a rare disease characterized by remodeling of the small pulmonary arteries leading to progressive elevation of pulmonary vascular resistance, ultimately leading to right ventricular failure and death. Deleterious mutations in the serine-threonine receptor bone morphogenetic protein receptor 2 (BMPR2; a central mediator of bone morphogenetic protein (BMP) signaling) and female sex are known risk factors for the development of PAH in humans.
    [Show full text]
  • Lineage Transcription Factors Co-Regulate Subtype-Specific Genes Providing a Roadmap For
    bioRxiv preprint doi: https://doi.org/10.1101/2020.08.13.249029; this version posted August 14, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Lineage transcription factors co-regulate subtype-specific genes providing a roadmap for systematic identification of small cell lung cancer vulnerabilities Karine Pozo1,2, Rahul K. Kollipara3, Demetra P. Kelenis1, Kathia E. Rodarte1, Xiaoyang Zhang4, John D. Minna5,6,7,8 and Jane E. Johnson1,6,8 1Department of Neuroscience, 2Department of Surgery, 3McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, TX 75390, USA 4Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 5Hamon Center for Therapeutic Oncology Research, 6Simmons Comprehensive Cancer Center, 7Department of Internal Medicine, 8Department of Pharmacology, UT Southwestern Medical Center, Dallas, TX 75390, USA JDM receives licensing fees for lung cancer lines from the NIH and UT Southwestern. 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.08.13.249029; this version posted August 14, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. ABSTRACT Lineage-defining transcription factors (LTFs) play key roles in tumor cell growth, making them highly attractive, but currently “undruggable”, small cell lung cancer (SCLC) vulnerabilities.
    [Show full text]
  • High Dimensional Single-Cell Analysis Reveals Inkt Cell Developmental
    bioRxiv preprint doi: https://doi.org/10.1101/2020.05.12.070425; this version posted May 12, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 High dimensional single-cell analysis reveals iNKT cell developmental trajectories and 2 effector fate decision 3 4 Thomas Baranek1,2,9, Kevin Lebrigand3, Carolina de Amat Herbozo4, Loïc Gonzalez1,2, Gemma 5 Bogard1,2, Céline Dietrich5, Virginie Magnone3, Chloé Boisseau1,2, Youenn Jouan1,2,6, François 6 Trottein7, Mustapha Si-Tahar1,2, Maria Leite-de-Moraes5, Thierry Mallevaey4,8, Christophe 7 Paget1,2,9,10 8 9 1INSERM, Centre d’Etude des Pathologies Respiratoires (CEPR), UMR 1100, Tours, France. 10 2Université de Tours, Faculté de Médecine de Tours, France. 11 3Université Côte d'Azur, CNRS, IPMC, Sophia-Antipolis, France. 12 4Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada. 13 5Université de Paris, Paris, France; Laboratory of Immunoregulation and Immunopathology, 14 INEM (Institut Necker-Enfants Malades), CNRS UMR8253 and INSERM UMR1151, Paris, 15 France. 16 6Service de Médecine Intensive et Réanimation, Centre Hospitalier Régional Universitaire, 17 Tours, France. 18 7Centre d’Infection et d’Immunité de Lille, Inserm U1019, CNRS UMR 9017, University of 19 Lille, CHU Lille- Institut Pasteur de Lille, 59000 Lille, France. 20 8Institute of Biomaterials & Biomedical Engineering, Toronto, Ontario M5S 1A8, Canada. 21 9Correspondance: [email protected] or [email protected] 22 10Lead contact 23 24 Keywords: iNKT cells; single cell RNA-sequencing; thymus; developmental program; 25 transcriptome; FHL2.
    [Show full text]
  • 7648.Full.Pdf
    The Journal of Neuroscience, October 15, 2000, 20(20):7648–7656 Evidence That Helix-Loop-Helix Proteins Collaborate with Retinoblastoma Tumor Suppressor Protein to Regulate Cortical Neurogenesis Jean G. Toma, Hiba El-Bizri, Fanie Barnabe´ -Heider, Raquel Aloyz, and Freda D. Miller Center for Neuronal Survival, Montreal Neurological Institute, Montreal, Canada H3A 2B4 The retinoblastoma tumor suppressor protein (pRb) family is phenotypes were rescued by coexpression of a constitutively essential for cortical progenitors to exit the cell cycle and survive. activated pRb mutant. In contrast, Id2 overexpression in post- In this report, we test the hypothesis that pRb collaborates with mitotic cortical neurons affected neither neuronal gene expres- basic helix-loop-helix (bHLH) transcription factors to regulate sion nor survival. Thus, pRb collaborates with HLHs to ensure the cortical neurogenesis, taking advantage of the naturally occur- coordinate induction of terminal mitosis and neuronal gene ex- ring dominant-inhibitory HLH protein Id2. Overexpression of Id2 pression as cortical progenitors become neurons. in cortical progenitors completely inhibited the induction of Key words: neurogenesis; Id2; pRb; bHLH transcription fac- neuron-specific genes and led to apoptosis, presumably as a tors; cortical development; neuronal gene expression; ␣-tubulin; consequence of conflicting differentiation signals. Both of these neural progenitor cells; neurofilaments; apoptosis During embryogenesis, cycling neural progenitor cells in the ven- In particular, in the PNS, bHLHs such as Mash-1 (Johnson et al., tricular zones of the CNS commit to a neuronal fate, and as a 1990) and the neurogenins (Ma et al., 1996; Sommer et al., 1996) consequence of that decision, coordinately undergo terminal mito- regulate the genesis of defined neuronal populations (Guillemot et sis and induce early, neuron-specific genes.
    [Show full text]
  • Dnmt1 Is Required for Proximal-Distal Patterning of the Lung Endoderm and for Restraining Alveolar Type 2 Cell Fate
    Developmental Biology 454 (2019) 108–117 Contents lists available at ScienceDirect Developmental Biology journal homepage: www.elsevier.com/locate/developmentalbiology Original research article Dnmt1 is required for proximal-distal patterning of the lung endoderm and for restraining alveolar type 2 cell fate Derek C. Liberti a,b,c,1, Jarod A. Zepp b,c,1, Christina A. Bartoni b,c, Kyle H. Liberti d, Su Zhou c, Minmin Lu c, Michael P. Morley b,c, Edward E. Morrisey a,b,c,e,f,* a Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA b Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA, 19104, USA c Penn Center for Pulmonary Biology, University of Pennsylvania, Philadelphia, PA, 19104, USA d Middleware Engineering, Red Hat, Westford, MA, 01886, USA e Department of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA f Penn-CHOP Lung Biology Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA ABSTRACT Lung endoderm development occurs through a series of finely coordinated transcriptional processes that are regulated by epigenetic mechanisms. However, the role of DNA methylation in regulating lung endoderm development remains poorly understood. We demonstrate that DNA methyltransferase 1 (Dnmt1) is required for early branching morphogenesis of the lungs and for restraining epithelial fate specification. Loss of Dnmt1 leads to an early branching defect, a loss of epithelial polarity and proximal endodermal cell differentiation, and an expansion of the distal endoderm compartment. Dnmt1 deficiency also disrupts epithelial-mesenchymal crosstalk and leads to precocious distal endodermal cell differentiation with premature expression of alveolar type 2 cell restricted genes.
    [Show full text]