Temporal Epigenomic Profiling Identifies AHR As a Dynamic Super-Enhancer Controlled Regulator of Mesenchymal Multipotency
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A B Previously-induced Doxycycline-naïve survival (%) survival (%) Recurrence-free Recurrence-free Days following dox withdrawal Age C D Primary Recurrent ** Par-4 mRNA H2B-mCherry DAPI Primary Recurrent Supplemental Figure 1: Recurrent tumors are derived from primary tumors. A. Kaplan-Meier survival plot showing recurrent tumor-free survival in mice previously induced with doxycycline (n=30) or tumor-free survival in doxycycline-naïve mice (n=10). B. Kaplan-Meier survival plot showing recurrence-free survival following doxycycline withdrawal in a cohort of recipient mice with orthotopic tumors (n=5). C. Representative images (40x magnification) of primary and recurrent orthotopic tumors following injection of H2B-mCherry labeled primary tumor cell line #1 into recipient mice. D. qRT-PCR analysis of Par-4 transcripts from primary (n=5) and recurrent (n=5) orthotopic tumors. Significance determined by Student’s t-test. Error bars denote mean ± SEM. **p<0.01. A B 1 TWIST1 TWIST2 0.5 SNAI2 0 VIM -0.5 ZEB1 ZEB2 -1 SNAI1 PAWR Positively correlated Negatively correlated with Par-4 with Par-4 CDH1 CLDN7 CLDN4 CLDN3 KRT18 NES = -2.07335 q-value = 0.001129 KRT8 TWIST1 TWIST2 SNAI2 VIM ZEB1 ZEB2 SNAI1 PAWR CDH1 CLDN7 CLDN4 CLDN3 KRT18 KRT8 Marcotte, et al. C 1 SNAI1 0.5 TWIST1 TWIST2 0 VIM -0.5 SNAI2 -1 ZEB1 ZEB2 PAWR CDH1 KRT18 KRT8 CLDN7 CLDN3 CLDN4 SNAI1 TWIST1 TWIST2 VIM SNAI2 ZEB1 ZEB2 PAWR CDH1 KRT18 KRT8 CLDN7 CLDN3 CLDN4 TCGA, Cell 2015 Supplemental Figure 2: Par-4 expression is negatively correlated with EMT in human breast cancer. A. -
Krüppel-Like Transcription Factor KLF10 Suppresses Tgfβ-Induced
Published OnlineFirst March 1, 2017; DOI: 10.1158/0008-5472.CAN-16-2589 Cancer Molecular and Cellular Pathobiology Research Kruppel-like€ Transcription Factor KLF10 Suppresses TGFb-Induced Epithelial-to- Mesenchymal Transition via a Negative Feedback Mechanism Vivek Kumar Mishra1, Malayannan Subramaniam2, Vijayalakshmi Kari1, Kevin S. Pitel2, Simon J. Baumgart1, Ryan M. Naylor2, Sankari Nagarajan1, Florian Wegwitz1, Volker Ellenrieder3, John R. Hawse2, and Steven A. Johnsen1 Abstract TGFb–SMAD signaling exerts a contextual effect that sup- sequences in the promoter region of the EMT-promoting tran- presses malignant growth early in epithelial tumorigenesis but scription factor SLUG/SNAI2, repressing its transcription by promotes metastasis at later stages. Longstanding challenges in recruiting HDAC1 and licensing the removal of activating resolving this functional dichotomy may uncover new strate- histone acetylation marks. In clinical specimens of lung ade- gies to treat advanced carcinomas. The Kruppel-like€ transcrip- nocarcinoma, low KLF10 expression associated with decreased tion factor, KLF10, is a pivotal effector of TGFb/SMAD signaling patient survival, consistent with a pivotal role for KLF10 in that mediates antiproliferative effects of TGFb.Inthisstudy,we distinguishing the antiproliferative versus prometastatic func- show how KLF10 opposes the prometastatic effects of TGFb tions of TGFb. Our results establish that KLF10 functions to by limiting its ability to induce epithelial-to-mesenchymal suppress TGFb-induced EMT, establishing a molecular basis for transition (EMT). KLF10 depletion accentuated induction of the dichotomy of TGFb function during tumor progression. EMT as assessed by multiple metrics. KLF10 occupied GC-rich Cancer Res; 77(9); 1–14. Ó2017 AACR. Introduction onic development and is indispensable for tissue and organ development in multicellular organisms (4). -
Machine-Learning and Chemicogenomics Approach Defi Nes and Predicts Cross-Talk of Hippo and MAPK Pathways
Published OnlineFirst November 18, 2020; DOI: 10.1158/2159-8290.CD-20-0706 RESEARCH ARTICLE Machine -Learning and Chemicogenomics Approach Defi nes and Predicts Cross-Talk of Hippo and MAPK Pathways Trang H. Pham 1 , Thijs J. Hagenbeek 1 , Ho-June Lee 1 , Jason Li 2 , Christopher M. Rose 3 , Eva Lin 1 , Mamie Yu 1 , Scott E. Martin1 , Robert Piskol 2 , Jennifer A. Lacap 4 , Deepak Sampath 4 , Victoria C. Pham 3 , Zora Modrusan 5 , Jennie R. Lill3 , Christiaan Klijn 2 , Shiva Malek 1 , Matthew T. Chang 2 , and Anwesha Dey 1 ABSTRACT Hippo pathway dysregulation occurs in multiple cancers through genetic and non- genetic alterations, resulting in translocation of YAP to the nucleus and activation of the TEAD family of transcription factors. Unlike other oncogenic pathways such as RAS, defi ning tumors that are Hippo pathway–dependent is far more complex due to the lack of hotspot genetic alterations. Here, we developed a machine-learning framework to identify a robust, cancer type–agnostic gene expression signature to quantitate Hippo pathway activity and cross-talk as well as predict YAP/TEAD dependency across cancers. Further, through chemical genetic interaction screens and multiomics analyses, we discover a direct interaction between MAPK signaling and TEAD stability such that knockdown of YAP combined with MEK inhibition results in robust inhibition of tumor cell growth in Hippo dysregulated tumors. This multifaceted approach underscores how computational models combined with experimental studies can inform precision medicine approaches including predictive diagnostics and combination strategies. SIGNIFICANCE: An integrated chemicogenomics strategy was developed to identify a lineage- independent signature for the Hippo pathway in cancers. -
Transcriptomic Analysis of Pluripotent Stem Cells: Insights Into Health and Disease Jia-Chi Yeo1,2 and Huck-Hui Ng1,2,3,4,5,*
Yeo and Ng Genome Medicine 2011, 3:68 http://genomemedicine.com/content/3/10/68 REVIEW Transcriptomic analysis of pluripotent stem cells: insights into health and disease Jia-Chi Yeo1,2 and Huck-Hui Ng1,2,3,4,5,* Abstract types, termed ‘pluripotency’, allows researchers to study early mammalian development in an artificial setting and Embryonic stem cells (ESCs) and induced pluripotent offers opportunities for regenerative medicine, whereby stem cells (iPSCs) hold tremendous clinical potential ESCs could generate clinically relevant cell types for because of their ability to self-renew, and to tissue repair. However, this same malleability of ESCs dierentiate into all cell types of the body. This unique also renders it a challenge to obtain in vitro differentiation capacity of ESCs and iPSCs to form all cell lineages of ESCs to specific cell types at high efficacy. erefore, is termed pluripotency. While ESCs and iPSCs are harnessing the full potential of ESCs requires an in-depth pluripotent and remarkably similar in appearance, understanding of the factors and mechanisms regulating whether iPSCs truly resemble ESCs at the molecular ESC pluripotency and cell lineage decisions. level is still being debated. Further research is therefore Early studies on ESCs led to the discovery of the core needed to resolve this issue before iPSCs may be safely pluripotency factors Oct4, Sox2 and Nanog [1], and, applied in humans for cell therapy or regenerative increasingly, the use of genome-level screening assays has medicine. Nevertheless, the use of iPSCs as an in vitro revealed new insights by uncovering additional trans- human genetic disease model has been useful in cription factors, transcriptional cofactors and chromatin studying the molecular pathology of complex genetic remodeling complexes involved in the maintenance of diseases, as well as facilitating genetic or drug screens. -
Molecular and Physiological Basis for Hair Loss in Near Naked Hairless and Oak Ridge Rhino-Like Mouse Models: Tracking the Role of the Hairless Gene
University of Tennessee, Knoxville TRACE: Tennessee Research and Creative Exchange Doctoral Dissertations Graduate School 5-2006 Molecular and Physiological Basis for Hair Loss in Near Naked Hairless and Oak Ridge Rhino-like Mouse Models: Tracking the Role of the Hairless Gene Yutao Liu University of Tennessee - Knoxville Follow this and additional works at: https://trace.tennessee.edu/utk_graddiss Part of the Life Sciences Commons Recommended Citation Liu, Yutao, "Molecular and Physiological Basis for Hair Loss in Near Naked Hairless and Oak Ridge Rhino- like Mouse Models: Tracking the Role of the Hairless Gene. " PhD diss., University of Tennessee, 2006. https://trace.tennessee.edu/utk_graddiss/1824 This Dissertation is brought to you for free and open access by the Graduate School at TRACE: Tennessee Research and Creative Exchange. It has been accepted for inclusion in Doctoral Dissertations by an authorized administrator of TRACE: Tennessee Research and Creative Exchange. For more information, please contact [email protected]. To the Graduate Council: I am submitting herewith a dissertation written by Yutao Liu entitled "Molecular and Physiological Basis for Hair Loss in Near Naked Hairless and Oak Ridge Rhino-like Mouse Models: Tracking the Role of the Hairless Gene." I have examined the final electronic copy of this dissertation for form and content and recommend that it be accepted in partial fulfillment of the requirements for the degree of Doctor of Philosophy, with a major in Life Sciences. Brynn H. Voy, Major Professor We have read this dissertation and recommend its acceptance: Naima Moustaid-Moussa, Yisong Wang, Rogert Hettich Accepted for the Council: Carolyn R. -
Sorting Nexins in Protein Homeostasis Sara E. Hanley1,And Katrina F
Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 6 November 2020 doi:10.20944/preprints202011.0241.v1 Sorting nexins in protein homeostasis Sara E. Hanley1,and Katrina F. Cooper2* 1Department of Molecular Biology, Graduate School of Biomedical Sciences, Rowan University, Stratford, NJ, 08084, USA 1 [email protected] 2 [email protected] * [email protected] Tel: +1 (856)-566-2887 1Department of Molecular Biology, Graduate School of Biomedical Sciences, Rowan University, Stratford, NJ, 08084, USA Abstract: Sorting nexins (SNXs) are a highly conserved membrane-associated protein family that plays a role in regulating protein homeostasis. This family of proteins is unified by their characteristic phox (PX) phosphoinositides binding domain. Along with binding to membranes, this family of SNXs also comprises a diverse array of protein-protein interaction motifs that are required for cellular sorting and protein trafficking. SNXs play a role in maintaining the integrity of the proteome which is essential for regulating multiple fundamental processes such as cell cycle progression, transcription, metabolism, and stress response. To tightly regulate these processes proteins must be expressed and degraded in the correct location and at the correct time. The cell employs several proteolysis mechanisms to ensure that proteins are selectively degraded at the appropriate spatiotemporal conditions. SNXs play a role in ubiquitin-mediated protein homeostasis at multiple levels including cargo localization, recycling, degradation, and function. In this review, we will discuss the role of SNXs in three different protein homeostasis systems: endocytosis lysosomal, the ubiquitin-proteasomal, and the autophagy-lysosomal system. The highly conserved nature of this protein family by beginning with the early research on SNXs and protein trafficking in yeast and lead into their important roles in mammalian systems. -
Glioblastoma Stem Cells Induce Quiescence in Surrounding Neural Stem Cells Via Notch Signalling
bioRxiv preprint doi: https://doi.org/10.1101/856062; this version posted November 29, 2019. 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. Glioblastoma stem cells induce quiescence in surrounding neural stem cells via Notch signalling. Katerina Lawlor1, Maria Angeles Marques-Torrejon2, Gopuraja Dharmalingham3, Yasmine El-Azhar1, Michael D. Schneider1, Steven M. Pollard2§ and Tristan A. Rodríguez1§ 1National Heart and Lung Institute, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, United Kingdom. 2 MRC Centre for Regenerative Medicine & Edinburgh Cancer Research UK Centre, University of Edinburgh, Edinburgh, UK. 3MRC London Institute of Medical Sciences, Institute of Clinical Sciences, Imperial College London, UK §Authors for correspondence: [email protected] and [email protected] Running title: Glioblastoma stem cell competition Keyword: Neural stem cells, quiescence, glioblastoma, Notch, cell competition 1 bioRxiv preprint doi: https://doi.org/10.1101/856062; this version posted November 29, 2019. 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 Abstract 2 There is increasing evidence suggesting that adult neural stem cells (NSCs) are a cell of 3 origin of glioblastoma, the most aggressive form of malignant glioma. The earliest stages of 4 hyperplasia are not easy to explore, but likely involve a cross-talk between normal and 5 transformed NSCs. How normal cells respond to this cross-talk and if they expand or are 6 outcompeted is poorly understood. -
Characterization of Cis-Regulatory Elements That Control Pax7
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Abstracts / Developmental Biology 331 (2009) 431–441 439 Program/Abstract # 169 Program/Abstract # 171 Characterization of cis-regulatory elements that control Pax7 Transcriptional regulation of Ptf1a in the developing nervous expression during neural crest cell development system Stephanie Vadasz, Martn Garca-Castro David M. Mereditha, Toshihiko Masuib, Galvin Swiftb, MCDB, Yale Univ., New Haven, CT, USA Raymond MacDonaldb, Jane E. Johnsona aDepartment of Neuroscience, UT Southwestern Med Center, Dallas, The neural crest is a population of multipotent migratory cells that TX, USA arises at the border between neural and non-neural ectoderm in bDepartment of Mol. Biol., UT Southwestern Med Center, Dallas, TX, USA vertebrates. It gives rise to many derivatives, including neurons and glia of the peripheral nervous system, melanocytes, and craniofacial Ptf1a, along with an E-protein and Rbpj, forms the transcription cartilage and bone. In the past two decades there has been a surge of factor complex PTF1-J that is essential for proper specification of efforts toward understanding neural crest induction, with several inhibitory neurons in the spinal cord, retina, and cerebellum. Ptf1a is the signaling pathways and tissue interactions being implicated. Recently, tissue specific component of this complex; therefore, understanding the transcription factor Pax7 was identified as an early marker of how Ptf1a expression is controlled provides critical insight into PTF1-J prospective neural crest cells and its functions shown to be required for regulation. Here we show that two highly conserved non-coding neural crest development. -
Functional Characterization of the New 8Q21 Asthma Risk Locus
Functional characterization of the new 8q21 Asthma risk locus Cristina M T Vicente B.Sc, M.Sc A thesis submitted for the degree of Doctor of Philosophy at The University of Queensland in 2017 Faculty of Medicine Abstract Genome wide association studies (GWAS) provide a powerful tool to identify genetic variants associated with asthma risk. However, the target genes for many allergy risk variants discovered to date are unknown. In a recent GWAS, Ferreira et al. identified a new association between asthma risk and common variants located on chromosome 8q21. The overarching aim of this thesis was to elucidate the biological mechanisms underlying this association. Specifically, the goals of this study were to identify the gene(s) underlying the observed association and to study their contribution to asthma pathophysiology. Using genetic data from the 1000 Genomes Project, we first identified 118 variants in linkage disequilibrium (LD; r2>0.6) with the sentinel allergy risk SNP (rs7009110) on chromosome 8q21. Of these, 35 were found to overlap one of four Putative Regulatory Elements (PREs) identified in this region in a lymphoblastoid cell line (LCL), based on epigenetic marks measured by the ENCODE project. Results from analysis of gene expression data generated for LCLs (n=373) by the Geuvadis consortium indicated that rs7009110 is associated with the expression of only one nearby gene: PAG1 - located 732 kb away. PAG1 encodes a transmembrane adaptor protein localized to lipid rafts, which is highly expressed in immune cells. Results from chromosome conformation capture (3C) experiments showed that PREs in the region of association physically interacted with the promoter of PAG1. -
Downloaded from JASPAR (JASPAR ID: MA0527.1) Across All Identified Peaks Using the Matrix-Scan Module from RSAT [20]
bioRxiv preprint doi: https://doi.org/10.1101/585653; this version posted March 24, 2019. 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. ZBTB33 (Kaiso) methylated binding sites are associated with primed heterochromatin Quy Xiao Xuan Lin1, Khadija Rebbani1, Sudhakar Jha1,2, Touati Benoukraf1,3* 1Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore 2Department of Biochemistry, National University of Singapore, Singapore, Singapore 3Discipline of Genetics, Faculty of Medicine, Memorial University of Newfoundland, St. John’s, NL, Canada *Correspondence to: Touati Benoukraf, Ph.D. Faculty of Medicine, Discipline of Genetics Cancer Science Institute of Singapore Craig L. Dobbin Genetics Research Centre National University of Singapore Room 5M317 Centre for Translational Medicine, Memorial University of Newfoundland 14 Medical Drive, #12-01 St. John's, NL A1B 3V6 Singapore 117599 Canada Phone: +1 (709) 864-6671 Email: [email protected] 1 bioRxiv preprint doi: https://doi.org/10.1101/585653; this version posted March 24, 2019. 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 Background: ZBTB33, also known as Kaiso, is a member of the zinc finger and BTB/POZ family. In contrast to many transcription factors, ZBTB33 has the ability to bind both a sequence-specific consensus and methylated DNA. -
Diverse Species-Specific Phenotypic Consequences of Loss of Function
www.nature.com/scientificreports OPEN Diverse species‑specifc phenotypic consequences of loss of function sorting nexin 14 mutations Dale Bryant1, Marian Seda1, Emma Peskett1, Constance Maurer1, Gideon Pomeranz1, Marcus Ghosh2, Thomas A. Hawkins2, James Cleak3, Sanchari Datta4, Hanaa Hariri4, Kaitlyn M. Eckert5,6, Daniyal J. Jafree1, Claire Walsh7, Charalambos Demetriou1, Miho Ishida1, Cristina Alemán‑Charlet1, Letizia Vestito1, Rimante Seselgyte1, Jefrey G. McDonald5,6, Maria Bitner‑Glindzicz1, Myriam Hemberger8, Jason Rihel2, Lydia Teboul3, W. Mike Henne4, Dagan Jenkins1, Gudrun E. Moore1 & Philip Stanier1* Mutations in the SNX14 gene cause spinocerebellar ataxia, autosomal recessive 20 (SCAR20) in both humans and dogs. Studies implicating the phenotypic consequences of SNX14 mutations to be consequences of subcellular disruption to autophagy and lipid metabolism have been limited to in vitro investigation of patient‑derived dermal fbroblasts, laboratory engineered cell lines and developmental analysis of zebrafsh morphants. SNX14 homologues Snz (Drosophila) and Mdm1 (yeast) have also been conducted, demonstrated an important biochemical role during lipid biogenesis. In this study we report the efect of loss of SNX14 in mice, which resulted in embryonic lethality around mid‑gestation due to placental pathology that involves severe disruption to syncytiotrophoblast cell diferentiation. In contrast to other vertebrates, zebrafsh carrying a homozygous, maternal zygotic snx14 genetic loss‑of‑function mutation were both viable and anatomically normal. Whilst no obvious behavioural efects were observed, elevated levels of neutral lipids and phospholipids resemble previously reported efects on lipid homeostasis in other species. The biochemical role of SNX14 therefore appears largely conserved through evolution while the consequences of loss of function varies between species. -
Increased HOXA5 Expression Provides a Selective Advantage for Gain of Whole Chromosome 7 in IDH Wild-Type Glioblastoma
Downloaded from genesdev.cshlp.org on May 11, 2018 - Published by Cold Spring Harbor Laboratory Press Increased HOXA5 expression provides a selective advantage for gain of whole chromosome 7 in IDH wild-type glioblastoma Patrick J. Cimino,1,2,17 Youngmi Kim,1,17 Hua-Jun Wu,3,4,5 Jes Alexander,1 Hans-Georg Wirsching,1,6 Frank Szulzewsky,1 Ken Pitter,7 Tatsuya Ozawa,1,8 Jiguang Wang,9,10,16 Julio Vazquez,11 Sonali Arora,1 Raul Rabadan,9,10 Ross Levine,12 Franziska Michor,3,4,5,13,14,15 and Eric C. Holland1 1Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA; 2Department of Pathology, Division of Neuropathology, University of Washington, Seattle, Washington 98104, USA; 3Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02215, USA; 4Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02115, USA; 5Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts 02138, USA; 6Department of Neurology, University Hospital Zurich, Zurich 8091, Switzerland; 7Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA; 8Division of Brain Tumor Translational Research, National Cancer Center Research Institute, Tokyo 104-0045, Japan; 9Department of Biomedical Informatics, Columbia University, New York, New York 10027, USA; 10Department of Systems Biology, Columbia University, New York,