Bmi1 – a Path to Targeting Cancer Stem Cells
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A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated. -
4-6 Weeks Old Female C57BL/6 Mice Obtained from Jackson Labs Were Used for Cell Isolation
Methods Mice: 4-6 weeks old female C57BL/6 mice obtained from Jackson labs were used for cell isolation. Female Foxp3-IRES-GFP reporter mice (1), backcrossed to B6/C57 background for 10 generations, were used for the isolation of naïve CD4 and naïve CD8 cells for the RNAseq experiments. The mice were housed in pathogen-free animal facility in the La Jolla Institute for Allergy and Immunology and were used according to protocols approved by the Institutional Animal Care and use Committee. Preparation of cells: Subsets of thymocytes were isolated by cell sorting as previously described (2), after cell surface staining using CD4 (GK1.5), CD8 (53-6.7), CD3ε (145- 2C11), CD24 (M1/69) (all from Biolegend). DP cells: CD4+CD8 int/hi; CD4 SP cells: CD4CD3 hi, CD24 int/lo; CD8 SP cells: CD8 int/hi CD4 CD3 hi, CD24 int/lo (Fig S2). Peripheral subsets were isolated after pooling spleen and lymph nodes. T cells were enriched by negative isolation using Dynabeads (Dynabeads untouched mouse T cells, 11413D, Invitrogen). After surface staining for CD4 (GK1.5), CD8 (53-6.7), CD62L (MEL-14), CD25 (PC61) and CD44 (IM7), naïve CD4+CD62L hiCD25-CD44lo and naïve CD8+CD62L hiCD25-CD44lo were obtained by sorting (BD FACS Aria). Additionally, for the RNAseq experiments, CD4 and CD8 naïve cells were isolated by sorting T cells from the Foxp3- IRES-GFP mice: CD4+CD62LhiCD25–CD44lo GFP(FOXP3)– and CD8+CD62LhiCD25– CD44lo GFP(FOXP3)– (antibodies were from Biolegend). In some cases, naïve CD4 cells were cultured in vitro under Th1 or Th2 polarizing conditions (3, 4). -
Genome-Wide Association Study for Circulating Fibroblast Growth Factor
www.nature.com/scientificreports OPEN Genome‑wide association study for circulating fbroblast growth factor 21 and 23 Gwo‑Tsann Chuang1,2,14, Pi‑Hua Liu3,4,14, Tsui‑Wei Chyan5, Chen‑Hao Huang5, Yu‑Yao Huang4,6, Chia‑Hung Lin4,7, Jou‑Wei Lin8, Chih‑Neng Hsu8, Ru‑Yi Tsai8, Meng‑Lun Hsieh9, Hsiao‑Lin Lee9, Wei‑shun Yang2,9, Cassianne Robinson‑Cohen10, Chia‑Ni Hsiung11, Chen‑Yang Shen12,13 & Yi‑Cheng Chang2,9,12* Fibroblast growth factors (FGFs) 21 and 23 are recently identifed hormones regulating metabolism of glucose, lipid, phosphate and vitamin D. Here we conducted a genome‑wide association study (GWAS) for circulating FGF21 and FGF23 concentrations to identify their genetic determinants. We enrolled 5,000 participants from Taiwan Biobank for this GWAS. After excluding participants with diabetes mellitus and quality control, association of single nucleotide polymorphisms (SNPs) with log‑transformed FGF21 and FGF23 serum concentrations adjusted for age, sex and principal components of ancestry were analyzed. A second model additionally adjusted for body mass index (BMI) and a third model additionally adjusted for BMI and estimated glomerular fltration rate (eGFR) were used. A total of 4,201 participants underwent GWAS analysis. rs67327215, located within RGS6 (a gene involved in fatty acid synthesis), and two other SNPs (rs12565114 and rs9520257, located between PHC2-ZSCAN20 and ARGLU1-FAM155A respectively) showed suggestive associations with serum FGF21 level (P = 6.66 × 10–7, 6.00 × 10–7 and 6.11 × 10–7 respectively). The SNPs rs17111495 and rs17843626 were signifcantly associated with FGF23 level, with the former near PCSK9 gene and the latter near HLA-DQA1 gene (P = 1.04 × 10–10 and 1.80 × 10–8 respectively). -
Polycomb Group Protein Expression During Differentiation of Human
Pethe et al. BMC Cell Biology 2014, 15:18 http://www.biomedcentral.com/1471-2121/15/18 RESEARCH ARTICLE Open Access Polycomb group protein expression during differentiation of human embryonic stem cells into pancreatic lineage in vitro Prasad Pethe, Punam Nagvenkar and Deepa Bhartiya* Abstract Background: Polycomb Group (PcG) proteins are chromatin modifiers involved in early embryonic development as well as in proliferation of adult stem cells and cancer cells. PcG proteins form large repressive complexes termed Polycomb Repressive Complexes (PRCs) of which PRC1 and PRC2 are well studied. Differentiation of human Embryonic Stem (hES) cells into insulin producing cells has been achieved to limited extent, but several aspects of differentiation remain unexplored. The PcG protein dynamics in human embryonic stem (hES) cells during differentiation into pancreatic lineage has not yet been reported. In the present study, the expression of RING1A, RING1B, BMI1, CBX2, SUZ12, EZH2, EED and JARID2 during differentiation of hES cells towards pancreatic lineage was examined. Results: In-house derived hES cell line KIND1 was used to study expression of PcG protein upon spontaneous and directed differentiation towards pancreatic lineage. qRT-PCR analysis showed expression of gene transcripts for various lineages in spontaneously differentiated KIND1 cells, but no differentiation into pancreatic lineage was observed. Directed differentiation induced KIND1 cells grown under feeder-free conditions to transition from definitive endoderm (Day 4), primitive gut tube stage (Day 8) and pancreatic progenitors (Day 12-Day 16) as evident from expression of SOX17, PDX1 and SOX9 by qRT-PCR and Western blotting. In spontaneously differentiating KIND1 cells, RING1A and SUZ12 were upregulated at day 15, while other PcG transcripts were downregulated. -
Polycomb Repressor Complex 1 Promotes Gene Silencing Through H2AK119 Mono-Ubiquitination in Acinar-To-Ductal Metaplasia and Pancreatic Cancer Cells
www.impactjournals.com/oncotarget/ Oncotarget, Vol. 7, No. 10 Polycomb repressor complex 1 promotes gene silencing through H2AK119 mono-ubiquitination in acinar-to-ductal metaplasia and pancreatic cancer cells Simone Benitz1,*, Ivonne Regel1,3,*, Tobias Reinhard1, Anna Popp1, Isabell Schäffer1, Susanne Raulefs1, Bo Kong1, Irene Esposito3, Christoph W. Michalski2,*, Jörg Kleeff1,4,5,* 1Department of Surgery, Technische Universität München, Munich, Germany 2Department of Surgery, University of Heidelberg, Heidelberg, Germany 3Institute of Pathology, Heinrich-Heine University, Duesseldorf, Germany 4The Royal Liverpool and Broadgreen University Hospitals, Liverpool, United Kingdom 5Department of Surgery, Heinrich-Heine University, Duesseldorf, Germany *These authors contribute equally to the manuscript. Correspondence to: Ivonne Regel, e-mail: [email protected] Keywords: polycomb repressor complex, histone mono-ubiquitination, pancreatic cancer, differentiation gene silencing Abbreviations: ADM (acinar-to-ductal metaplasia), PDAC (pancreatic ductal adenocarcinoma), PRC (polycomb repressor complex), PTF (pancreas specific transcription factor) Received: July 29, 2015 Accepted: November 16, 2015 Published: December 22, 2015 ABSTRACT Acinar-to-ductal metaplasia (ADM) occurring in cerulein-mediated pancreatitis or in oncogenic Kras-driven pancreatic cancer development is accompanied by extensive changes in the transcriptional program. In this process, acinar cells shut down the expression of acinar specific differentiation genes -
PHC1 Maintains Pluripotency by Organizing Genome-Wide Chromatin Interactions of the Nanog Locus
ARTICLE https://doi.org/10.1038/s41467-021-22871-0 OPEN PHC1 maintains pluripotency by organizing genome-wide chromatin interactions of the Nanog locus Li Chen1,2,3,14, Qiaoqiao Tong1,2,3,14, Xiaowen Chen4,14, Penglei Jiang1,2, Hua Yu1,2, Qianbing Zhao1,2,3, Lingang Sun1,2,3, Chao Liu 1,2,3,5, Bin Gu6, Yuping Zheng 7, Lijiang Fei1,2,3, Xiao Jiang8, Wenjuan Li9,10, Giacomo Volpe 9,10, Mazid MD. Abdul9,10, Guoji Guo 1,2,3, Jin Zhang1,2, Pengxu Qian1,2, Qiming Sun 8, ✉ ✉ ✉ Dante Neculai 7, Miguel A. Esteban9,10,11, Chen Li 12 , Feiqiu Wen4 & Junfeng Ji 1,2,3,13 1234567890():,; Polycomb group (PcG) proteins maintain cell identity by repressing gene expression during development. Surprisingly, emerging studies have recently reported that a number of PcG proteins directly activate gene expression during cell fate determination process. However, the mechanisms by which they direct gene activation in pluripotency remain poorly under- stood. Here, we show that Phc1, a subunit of canonical polycomb repressive complex 1 (cPRC1), can exert its function in pluripotency maintenance via a PRC1-independent activa- tion of Nanog. Ablation of Phc1 reduces the expression of Nanog and overexpression of Nanog partially rescues impaired pluripotency caused by Phc1 depletion. We find that Phc1 interacts with Nanog and activates Nanog transcription by stabilizing the genome-wide chromatin interactions of the Nanog locus. This adds to the already known canonical function of PRC1 in pluripotency maintenance via a PRC1-dependent repression of differentiation genes. Overall, our study reveals a function of Phc1 to activate Nanog transcription through regulating chromatin architecture and proposes a paradigm for PcG proteins to maintain pluripotency. -
Ezh2, the Histone Methyltransferase of PRC2, Regulates the Balance Between Self-Renewal and Differentiation in the Cerebral Cortex
Ezh2, the histone methyltransferase of PRC2, regulates the balance between self-renewal and differentiation in the cerebral cortex João D. Pereiraa, Stephen N. Sansoma, James Smitha, Marc-Werner Dobeneckerb, Alexander Tarakhovskyb, and Frederick J. Liveseya,1 aGurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge CB2 1QN, United Kingdom; and bLaboratory of Lymphocyte Signaling, The Rockefeller University, New York, NY 10021 Edited by Gerald R. Crabtree, Howard Hughes Medical Institute, Stanford, CA, and approved August 4, 2010 (received for review February 26, 2010) Multipotent progenitor cells of the cerebral cortex balance self- Knockout of the Bmi1 subunit of PRC1 has little effect on renewal and differentiation to produce complex neural lineages in progenitor cell self-renewal during development but is essential for a fixed temporal order in a cell-autonomous manner. We studied neural stem cell maintenance in the adult CNS (19). However, the role of the polycomb epigenetic system, a chromatin-based acute deletion of Bmi1 by RNAi does compromise cortical pro- repressive mechanism, in controlling cortical progenitor cell self- genitor cell self-renewal (20). Furthermore, removal of Ring1B, an renewal and differentiation. We found that the histone methyl- ubiquitin ligase component of PRC1, from the developing cortex transferase of polycomb repressive complex 2 (PCR2), enhancer of during neurogenesis lengthens the period of neurogenesis and Zeste homolog 2 (Ezh2), is essential for controlling the rate at -
SOX9 Promotes Tumor Progression Through the Axis BMI1-P21cip
www.nature.com/scientificreports OPEN SOX9 promotes tumor progression through the axis BMI1-p21CIP Paula Aldaz1,7, Maddalen Otaegi-Ugartemendia1,7, Ander Saenz-Antoñanzas1, Mikel Garcia- Puga1, Manuel Moreno-Valladares1,2, Juana M. Flores3, Daniela Gerovska4, Marcos J. Arauzo- Bravo 4,5,6, Nicolas Samprón1,2,5, Ander Matheu1,5,6* & Estefania Carrasco-Garcia1* The developmental regulator SOX9 is linked to cancer progression mainly as a result of its role in the regulation of cancer stem cells (CSCs). However, its activity in the diferentiated cells that constitute the heterogeneous tumor bulk has not been extensively studied. In this work, we addressed this aspect in gastric cancer, glioblastoma and pancreatic adenocarcinoma. SOX9 silencing studies revealed that SOX9 is required for cancer cell survival, proliferation and evasion of senescence in vitro and tumor growth in vivo. Gain of-SOX9 function showed that high levels of SOX9 promote tumor cell proliferation in vitro and in vivo. Mechanistically, the modulation of SOX9 changed the expression of the transcriptional repressor BMI1 in the same direction in the three types of cancer, and the expression of the tumor suppressor p21CIP in the opposite direction. In agreement with this, SOX9 expression positively correlated with BMI1 levels and inversely with p21CIP in clinical samples of the diferent cancers. Moreover, BMI1 re-establishment in SOX9-silenced tumor cells restored cell viability and proliferation as well as decreased p21CIP in vitro and tumor growth in vivo. These results indicate that BMI1 is a critical efector of the pro-tumoral activity of SOX9 in tumor bulk cells through the repression of p21CIP. -
Oncogenic Potential of BMI1: Race-Based Evidence in Prostate Cancer
Editorial Page 1 of 5 Oncogenic potential of BMI1: race-based evidence in prostate cancer Eswar Shankar1,2, Shiv Verma1, Sanjay Gupta1,2,3,4,5 1Department of Urology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA; 2The Urology Institute, University Hospitals Cleveland Medical Center, Cleveland, OH 44106, USA; 3Department of Urology, Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, OH 44106, USA; 4Department of Nutrition, Case Western Reserve University, Cleveland, OH 44106, USA; 5Division of General Medical Sciences, Case Comprehensive Cancer Center, Cleveland, OH 44106, USA Correspondence to: Sanjay Gupta, PhD. Department of Urology, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA. Email: [email protected]. Provenance: This is an invited Editorial commissioned by Section Editor Xiao Li (Department of Urologic Surgery, The Affiliated Cancer Hospital of Jiangsu Province of Nanjing Medical University, Nanjing, China). Comment on: Ganaie AA, Beigh FH, Astone M, et al. BMI1 Drives Metastasis of Prostate Cancer in Caucasian and African-American Men and Is A Potential Therapeutic Target: Hypothesis Tested in Race-specific Models. Clin Cancer Res 2018. [Epub ahead of print]. Received: 12 October 2018; Accepted: 02 November 2018; Published: 09 November 2018. doi: 10.21037/amj.2018.11.01 View this article at: http://dx.doi.org/10.21037/amj.2018.11.01 A recent publication by Ganaie et al. (1) in Clinical Cancer sequence between various species (4). The human BMI1 Research (doi: 10.1158/1078-0432.CCR-18-1394, 2018) gene is localized on chromosome 10 (10p11.23) (Figure 1A). demonstrate BMI1 as a potential driver of metastasis in The BMI1 protein comprises of 326 amino acids having prostate cancer. -
The Central Role of EED in the Orchestration of Polycomb Group Complexes
ARTICLE Received 22 Aug 2013 | Accepted 16 Dec 2013 | Published 24 Jan 2014 DOI: 10.1038/ncomms4127 The central role of EED in the orchestration of polycomb group complexes Qi Cao1,2,3,4, Xiaoju Wang1,2, Meng Zhao5, Rendong Yang5, Rohit Malik1,2, Yuanyuan Qiao1,2, Anton Poliakov1,2, Anastasia K. Yocum1, Yong Li1, Wei Chen1,6, Xuhong Cao1,7, Xia Jiang1,2, Arun Dahiya1, Clair Harris8, Felix Y. Feng1,6,9, Sundeep Kalantry8, Zhaohui S. Qin5,10, Saravana M. Dhanasekaran1,2 & Arul M. Chinnaiyan1,2,7,9,11 Polycomb repressive complexes 1 and 2 (PRC1 and 2) play a critical role in the epigenetic regulation of transcription during cellular differentiation, stem cell pluripotency and neoplastic progression. Here we show that the polycomb group protein EED, a core component of PRC2, physically interacts with and functions as part of PRC1. Components of PRC1 and PRC2 compete for EED binding. EED functions to recruit PRC1 to H3K27me3 loci and enhances PRC1-mediated H2A ubiquitin E3 ligase activity. Taken together, we suggest an integral role for EED as an epigenetic exchange factor coordinating the activities of PRC1 and 2. 1 Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA. 2 Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA. 3 Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, Texas 77030, USA. 4 Cancer Center, Houston Methodist Research Institute, Houston, Texas 77030, USA. 5 Department of Biostatistics and Bioinformatics, Emory University, Atlanta, Georgia 30329, USA. 6 Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA. -
Juxtaposed Polycomb Complexes Co-Regulate Vertebral Identity
RESEARCH ARTICLE 4957 Development 133, 4957-4968 (2006) doi:10.1242/dev.02677 Juxtaposed Polycomb complexes co-regulate vertebral identity Se Young Kim1, Suzanne W. Paylor1, Terry Magnuson2 and Armin Schumacher1,* Best known as epigenetic repressors of developmental Hox gene transcription, Polycomb complexes alter chromatin structure by means of post-translational modification of histone tails. Depending on the cellular context, Polycomb complexes of diverse composition and function exhibit cooperative interaction or hierarchical interdependency at target loci. The present study interrogated the genetic, biochemical and molecular interaction of BMI1 and EED, pivotal constituents of heterologous Polycomb complexes, in the regulation of vertebral identity during mouse development. Despite a significant overlap in dosage-sensitive homeotic phenotypes and co-repression of a similar set of Hox genes, genetic analysis implicated eed and Bmi1 in parallel pathways, which converge at the level of Hox gene regulation. Whereas EED and BMI1 formed separate biochemical entities with EzH2 and Ring1B, respectively, in mid-gestation embryos, YY1 engaged in both Polycomb complexes. Strikingly, methylated lysine 27 of histone H3 (H3-K27), a mediator of Polycomb complex recruitment to target genes, stably associated with the EED complex during the maintenance phase of Hox gene repression. Juxtaposed EED and BMI1 complexes, along with YY1 and methylated H3- K27, were detected in upstream regulatory regions of Hoxc8 and Hoxa5. The combined data suggest a model wherein epigenetic and genetic elements cooperatively recruit and retain juxtaposed Polycomb complexes in mammalian Hox gene clusters toward co- regulation of vertebral identity. KEY WORDS: Polycomb, eed, Bmi1, Hox genes, Mouse development, Chromatin, Histones, Epigenetics INTRODUCTION Wang, H. -
A High-Density Map for Navigating the Human Polycomb Complexome
Resource A High-Density Map for Navigating the Human Polycomb Complexome Graphical Abstract Authors Simon Hauri, Federico Comoglio, Makiko Seimiya, ..., Renato Paro, Matthias Gstaiger, Christian Beisel Correspondence [email protected] (M.G.), [email protected] (C.B.) In Brief Polycomb group (PcG) proteins mediate gene silencing and epigenetic memory in higher eukaryotes. By systematically mapping the human PcG complexome, Hauri et al. resolve Polycomb subcomplexes at high resolution and identify two human PRC2 and two PR- DUB complexes. Furthermore, genomic profiling reveals segregation of PRC1 and PR-DUB target genes. Highlights Accession Numbers d 1,400 high-confidence interactions reveal the modular GSE51673 organization of human PcG proteins d Detailed dissection of PRC1 and PRC2 subcomplexes d Two human PR-DUB complexes contain the glycosyltransferase OGT1 d PR-DUB and PRC1 bind largely distinct sets of target genes Hauri et al., 2016, Cell Reports 17, 583–595 October 4, 2016 ª 2016 The Authors. http://dx.doi.org/10.1016/j.celrep.2016.08.096 Cell Reports Resource A High-Density Map for Navigating the Human Polycomb Complexome Simon Hauri,1,2,7,8 Federico Comoglio,3,7,9 Makiko Seimiya,3 Moritz Gerstung,3,10 Timo Glatter,1,11 Klaus Hansen,4 Ruedi Aebersold,1,5 Renato Paro,3,6 Matthias Gstaiger,1,2,* and Christian Beisel3,12,* 1Department of Biology, Institute of Molecular Systems Biology, ETH Zurich,€ 8093 Zurich,€ Switzerland 2Competence Center Personalized Medicine UZH/ETH, 8044 Zurich,€ Switzerland 3Department