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Human Stem Cells from Single Blastomeres Reveal Pathways of Embryonic Or Trophoblast Fate Specification Tamara Zdravkovic1,2,3,4,5,‡, Kristopher L
© 2015. Published by The Company of Biologists Ltd | Development (2015) 142, 4010-4025 doi:10.1242/dev.122846 STEM CELLS AND REGENERATION RESEARCH ARTICLE Human stem cells from single blastomeres reveal pathways of embryonic or trophoblast fate specification Tamara Zdravkovic1,2,3,4,5,‡, Kristopher L. Nazor6,‡, Nicholas Larocque1,2,3,4,5, Matthew Gormley1,2,3,4,5, Matthew Donne1,2,3,7, Nathan Hunkapillar1,2,3,4,5, Gnanaratnam Giritharan8, Harold S. Bernstein4,9, Grace Wei4,10, Matthias Hebrok10, Xianmin Zeng11, Olga Genbacev1,2,3,4,5, Aras Mattis4,12, Michael T. McMaster4,5,13, Ana Krtolica8,*, Diana Valbuena14, Carlos Simón14, Louise C. Laurent6,15, Jeanne F. Loring6 and Susan J. Fisher1,2,3,4,5,7,§ ABSTRACT INTRODUCTION For many reasons, relatively little is known about human Mechanisms of initial cell fate decisions differ among species. To gain preimplantation development. The small number of cells makes insights into lineage allocation in humans, we derived ten human embryos of any species difficult to study. In humans, the technical embryonic stem cell lines (designated UCSFB1-10) from single difficulties are compounded by other challenges. Genetic variation blastomeres of four 8-cell embryos and one 12-cell embryo from a among individuals could contribute to developmental differences, a single couple. Compared with numerous conventional lines from well-appreciated phenomenon in the mouse (Dackor et al., 2009), blastocysts, they had unique gene expression and DNA methylation which is difficult to assess in humans owing to the limited patterns that were, in part, indicative of trophoblast competence. At a availability of embryos that are donated for research. -
NANOG and LIN28 Dramatically Improve Human Cell Reprogramming
© 2019. Published by The Company of Biologists Ltd | Biology Open (2019) 8, bio047225. doi:10.1242/bio.047225 RESEARCH ARTICLE NANOG and LIN28 dramatically improve human cell reprogramming by modulating LIN41 and canonical WNT activities Ling Wang, Yue Su, Chang Huang, Yexuan Yin, Alexander Chu, Alec Knupp and Young Tang* ABSTRACT (Hussein et al., 2014). The first transcriptional change occurs at the Human cell reprogramming remains extremely inefficient and the early reprogramming stage, with cells undergoing mesenchymal-to- underlying mechanisms by different reprogramming factors are epithelial transition (MET) for iPSC colony formation (Hussein elusive. We found that NANOG and LIN28 (NL) synergize to improve et al., 2014; Li et al., 2010; Samavarchi-Tehrani et al., 2010). This OCT4, SOX2, KLF4 and MYC (OSKM)-mediated reprogramming by stage is followed by the second wave that occurs during maturation ∼76-fold and shorten reprogramming latency by at least 1 week. This and stabilization, when the pluripotency regulatory network is synergy is inhibited by GLIS1 but reinforced by an inhibitor of the activated and stabilized in reprogrammed cells (Buganim et al., 2012; histone methyltransferase DOT1L (iDOT1L) to a ∼127-fold increase in Golipour et al., 2012; Hussein et al., 2014; Polo et al., 2012; TRA-1-60-positive (+) iPSC colonies. Mechanistically, NL serve as the Samavarchi-Tehrani et al., 2010). In human cells, the early-to-middle main drivers of reprogramming in cell epithelialization, the expression reprogramming stages are characterized by multiple waves of lineage- of Let-7 miRNA target LIN41, and the activation of canonical WNT/β- related gene activation in the order of developmental reversal, with CATENIN signaling, which can be further enhanced by iDOT1L MET occurring at the middle-to-late-reprogramming stage along with treatment. -
A Lncrna/Lin28/Mirlet7 Axis Coupled to DNA Methylation Fine Tunes the Dynamics of a Cell State Transition
bioRxiv preprint doi: https://doi.org/10.1101/131110; this version posted April 26, 2017. 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. Li, M.A. et al A lncRNA/Lin28/Mirlet7 axis coupled to DNA methylation fine tunes the dynamics of a cell state transition Meng Amy Li1*,2,#, Paulo P. Amaral3, Priscilla Cheung2, Jan H. Bergmann4,9, Masaki Kinoshita1, Tüzer Kalkan1, Meryem Ralser1, Sam Robson3, Ferdinand von Meyenn5, Maike Paramor1, Fengtang Yang6, Caifu Chen7, Jennifer Nichols1, David L. Spector4, Tony Kouzarides3, Lin He2,#, Austin Smith1,8,# 1. Wellcome Trust - Medical Research Council Stem Cell Institute, Tennis Court Road, University of Cambridge, Cambridge, CB2 1QR, UK 2. Division of Cellular and Developmental Biology, Department of Molecular and Cellular Biology, University of California Berkeley, Berkeley, California 94705, USA 3. The Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QN, UK 4. Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA 5. Babraham Institute, Babraham, Cambridge, CB22 3AT 6. Wellcome Trust Sanger Institute, Genome Campus, Hinxton, CB10 1SA, UK 7. Integrated DNA Technologies, 200 Chesapeake Drive, Redwood City, CA 94063, USA. 8. Department of Biochemistry, University of Cambridge, CB2 1QW, UK 9. Current address: Agenus inc., Hochbergerstrasse 60C, 4057 Basel, Switzerland *. Current address. # . Correspondence: [email protected], [email protected] and [email protected] Lead contact: Austin Smith Summary Execution of pluripotency requires progression from the naïve status represented by mouse embryonic stem cells (ESCs) to a condition poised for lineage specification. -
An Ontogenetic Switch Drives the Positive and Negative Selection of B Cells
An ontogenetic switch drives the positive and negative selection of B cells Xijin Xua, Mukta Deobagkar-Lelea, Katherine R. Bulla, Tanya L. Crockforda, Adam J. Meadb, Adam P. Cribbsc, David Simsc, Consuelo Anzilottia, and Richard J. Cornalla,1 aMedical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, OX3 9DS Oxford, United Kingdom; bMedical Research Council Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, OX3 9DS Oxford, United Kingdom; and cMedical Research Council, Weatherall Institute of Molecular Medicine, Centre for Computational Biology, Weatherall Institute of Molecular Medicine, University of Oxford, OX3 9DS Oxford, United Kingdom Edited by Michael Reth, University of Freiburg, Freiburg, Germany, and approved January 6, 2020 (received for review September 3, 2019) + Developing B cells can be positively or negatively selected by self- BM HSCs increased CD5 B-1a B cell development (15), while antigens, but the mechanisms that determine these outcomes are expression of let-7b in FL pro-B cells blocked the development of incompletely understood. Here, we show that a B cell intrinsic B-1 B cells (17). These findings support the notion of hard-wired switch between positive and negative selection during ontogeny differences during ontogeny, but possibly downstream of the HSC is determined by a change from Lin28b to let-7 gene expression. commitment stage. Ectopic expression of a Lin28b transgene in murine B cells restored Several lines of evidence also suggest that B-1 B cells can un- the positive selection of autoreactive B-1 B cells by self-antigen in dergo positive selection, which is linked to their B cell receptor adult bone marrow. -
METTL1 Promotes Let-7 Microrna Processing Via M7g Methylation
Article METTL1 Promotes let-7 MicroRNA Processing via m7G Methylation Graphical Abstract Authors Luca Pandolfini, Isaia Barbieri, Andrew J. Bannister, ..., Mara d’Onofrio, Shankar Balasubramanian, Tony Kouzarides Correspondence [email protected] In Brief Pandolfini, Barbieri, et al. show that a subgroup of tumor suppressor microRNAs, including let-7e, contain 7-methylguanosine (m7G). Methyltransferase METTL1 is required for m7G modification of miRNAs, their efficient processing, and the inhibition of lung cancer cell migration. Structurally, m7G in miRNA precursors antagonizes RNA secondary structures that would otherwise inhibit their maturation. Highlights Data Resource d Internal m7G is identified in miRNAs by two independent GSE112182 sequencing techniques GSE112180 GSE112181 d Methyltransferase METTL1 mediates m7G modification of GSE120454 specific miRNAs GSE120455 d METTL1 promotes miRNA maturation and suppresses lung cancer cell migration d m7G promotes processing by antagonizing G-quadruplex structures in miRNA precursors Pandolfini et al., 2019, Molecular Cell 74, 1278–1290 June 20, 2019 ª 2019 The Author(s). Published by Elsevier Inc. https://doi.org/10.1016/j.molcel.2019.03.040 Molecular Cell Article METTL1 Promotes let-7 MicroRNA Processing via m7G Methylation Luca Pandolfini,1,9 Isaia Barbieri,1,2,9 Andrew J. Bannister,1 Alan Hendrick,3 Byron Andrews,3 Natalie Webster,3 Pierre Murat,4,7 Pia Mach,1 Rossella Brandi,5 Samuel C. Robson,1,8 Valentina Migliori,1 Andrej Alendar,1 Mara d’Onofrio,5,6 Shankar Balasubramanian,4 -
Appendix 2. Significantly Differentially Regulated Genes in Term Compared with Second Trimester Amniotic Fluid Supernatant
Appendix 2. Significantly Differentially Regulated Genes in Term Compared With Second Trimester Amniotic Fluid Supernatant Fold Change in term vs second trimester Amniotic Affymetrix Duplicate Fluid Probe ID probes Symbol Entrez Gene Name 1019.9 217059_at D MUC7 mucin 7, secreted 424.5 211735_x_at D SFTPC surfactant protein C 416.2 206835_at STATH statherin 363.4 214387_x_at D SFTPC surfactant protein C 295.5 205982_x_at D SFTPC surfactant protein C 288.7 1553454_at RPTN repetin solute carrier family 34 (sodium 251.3 204124_at SLC34A2 phosphate), member 2 238.9 206786_at HTN3 histatin 3 161.5 220191_at GKN1 gastrokine 1 152.7 223678_s_at D SFTPA2 surfactant protein A2 130.9 207430_s_at D MSMB microseminoprotein, beta- 99.0 214199_at SFTPD surfactant protein D major histocompatibility complex, class II, 96.5 210982_s_at D HLA-DRA DR alpha 96.5 221133_s_at D CLDN18 claudin 18 94.4 238222_at GKN2 gastrokine 2 93.7 1557961_s_at D LOC100127983 uncharacterized LOC100127983 93.1 229584_at LRRK2 leucine-rich repeat kinase 2 HOXD cluster antisense RNA 1 (non- 88.6 242042_s_at D HOXD-AS1 protein coding) 86.0 205569_at LAMP3 lysosomal-associated membrane protein 3 85.4 232698_at BPIFB2 BPI fold containing family B, member 2 84.4 205979_at SCGB2A1 secretoglobin, family 2A, member 1 84.3 230469_at RTKN2 rhotekin 2 82.2 204130_at HSD11B2 hydroxysteroid (11-beta) dehydrogenase 2 81.9 222242_s_at KLK5 kallikrein-related peptidase 5 77.0 237281_at AKAP14 A kinase (PRKA) anchor protein 14 76.7 1553602_at MUCL1 mucin-like 1 76.3 216359_at D MUC7 mucin 7, -
Single Cell Regulatory Landscape of the Mouse Kidney Highlights Cellular Differentiation Programs and Disease Targets
ARTICLE https://doi.org/10.1038/s41467-021-22266-1 OPEN Single cell regulatory landscape of the mouse kidney highlights cellular differentiation programs and disease targets Zhen Miao 1,2,3,8, Michael S. Balzer 1,2,8, Ziyuan Ma 1,2,8, Hongbo Liu1,2, Junnan Wu 1,2, Rojesh Shrestha 1,2, Tamas Aranyi1,2, Amy Kwan4, Ayano Kondo 4, Marco Pontoglio 5, Junhyong Kim6, ✉ Mingyao Li 7, Klaus H. Kaestner2,4 & Katalin Susztak 1,2,4 1234567890():,; Determining the epigenetic program that generates unique cell types in the kidney is critical for understanding cell-type heterogeneity during tissue homeostasis and injury response. Here, we profile open chromatin and gene expression in developing and adult mouse kidneys at single cell resolution. We show critical reliance of gene expression on distal regulatory elements (enhancers). We reveal key cell type-specific transcription factors and major gene- regulatory circuits for kidney cells. Dynamic chromatin and expression changes during nephron progenitor differentiation demonstrates that podocyte commitment occurs early and is associated with sustained Foxl1 expression. Renal tubule cells follow a more complex differentiation, where Hfn4a is associated with proximal and Tfap2b with distal fate. Mapping single nucleotide variants associated with human kidney disease implicates critical cell types, developmental stages, genes, and regulatory mechanisms. The single cell multi-omics atlas reveals key chromatin remodeling events and gene expression dynamics associated with kidney development. 1 Renal, Electrolyte, and Hypertension Division, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA. 2 Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA. -
A KLF4/Pihl/EZH2/HMGA2 Regulatory Axis and Its Function in Promoting
Deng et al. Cell Death and Disease (2021) 12:485 https://doi.org/10.1038/s41419-021-03753-1 Cell Death & Disease ARTICLE Open Access A KLF4/PiHL/EZH2/HMGA2 regulatory axis and its function in promoting oxaliplatin-resistance of colorectal cancer Xuan Deng1, Fanyang Kong2,SiLi3,HaoqinJiang1,LiuDong1,XiaoXu1, Xinju Zhang1,HongYuan3,YingXu4, Yimin Chu4,HaixiaPeng4 andMingGuan 1 Abstract Long noncoding RNAs (lncRNAs) have emerged as a new class of regulatory molecules implicated in therapeutic resistance, yet the mechanisms underlying lncRNA-mediated oxaliplatin resistance in colorectal cancer (CRC) are poorly understood. In this study, lncRNA P53 inHibiting LncRNA (PiHL) was shown to be highly induced in oxaliplatin- resistant CRC cells and tumor tissues. In vitro and in vivo models clarified PiHL’s role in conferring resistance to oxaliplatin-induced apoptosis. PiHL antagonized chemosensitivity through binding with EZH2, repressing location of EZH2 to HMGA2 promoter, and downregulating methylation of histone H3 lysine 27 (H3K27me3) level in HMGA2 promoter, thus activating HMGA2 expression. Furthermore, HMGA2 upregulation induced by PiHL promotes PI3K/Akt phosphorylation, which resulted in increased oxaliplatin resistance. We also found that transcription factor KLF4 was downregulated in oxaliplatin-resistant cells, and KLF4 negatively regulated PiHL expression by binding to PiHL promoter. In vivo models further demonstrated that treatment of oxaliplatin-resistant CRC with locked nucleic acids targeting PiHL restored oxaliplatin response. Collectively, this study established lncRNA PiHL as a chemoresistance 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; promoter in CRC, and targeting PiHL/EZH2/HMGA2/PI3K/Akt signaling axis represents a novel choice in the investigation of drug resistance. Introduction eventually cause cell cycle arrest and apoptosis2. -
LIN28B Promotes the Development of Neuroendocrine Prostate Cancer
LIN28B promotes the development of neuroendocrine prostate cancer Jessica M. Lovnicki, … , Martin Gleave, Xuesen Dong J Clin Invest. 2020. https://doi.org/10.1172/JCI135373. Research In-Press Preview Oncology Graphical abstract Find the latest version: https://jci.me/135373/pdf LIN28B promotes the development of neuroendocrine prostate cancer Jessica Lovnicki1, *, Yu Gan1, 2, *, Tingting Feng1, 3, Yinan Li1, Ning Xie1, Chia-Hao Ho1, Ahn Lee1, Xufeng Chen4, Lucia Nappi1, Bo Han3, Ladan Fazli1, Jiaoti Huang4, Martin Gleave1, Xuesen Dong1 1) The Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada 2) Department of Urology, Xiangya Hospital, Central South University, Changsha, Hunan Province, China 3) The Key Laboratory of Experimental Teratology, Ministry of Education, and Department of Pathology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong Province, China 4) Department of Pathology, Duke University School of Medicine, Durham, North Carolina, USA *) The authors equally contribute to this work. Corresponding author: Xuesen Dong, Ph.D. 2660 Oak Street, Vancouver, British Columbia, Canada V6H 3Z6, Tel: 604-875-4111 Fax: 604-875-5654 Email: [email protected] Disclosure Statement: The authors have declared that no conflict of interest exists. 1 Abstract Therapy-induced neuroendocrine prostate cancer (t-NEPC) is a highly aggressive subtype of prostate cancer with poor patient survival. Emerging evidence indicates that t-NEPC can develop when prostate adenocarcinoma cells acquire cancer stem-like cell signaling in the presence of androgen receptor inhibition, followed by re-differentiation toward neuroendocrine lineage and subsequent t-NEPC progression. Whether the stem-like signaling is controlled by the core pluripotency stem cell genes (e.g., LIN28 and SOX2) remains unknown. -
Figure S17 Figure S16
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Supporting Information
Supporting Information Sutherland et al. 10.1073/pnas.1319963111 SI Materials and Methods (SPC) (rabbit polyclonal, 1:2,000, Chemicon), and anti-sex Histology and Immunohistochemistry. For histological analysis, determining region Y-box 2 (Sox2) (rabbit polyclonal, 1:1,000, lungs were inflated with ethanol–acetic acid–formalin (EAF) and Millipore). fixed for 24 h in EAF. Fixed tissues were subsequently dehy- Immunofluorescence Microscopy. For immunofluorescence mi- drated, embedded in paraffin, and sections (4 μm) prepared and + croscopy, Ad5–Cre-infected K-Raslox-Stop-lox-G12D/ lungs were stained by hematoxylin and eosin (H&E). For immunohisto- inflated and fixed with EAF overnight. Fixed lungs were em- chemistry, tissue sections were rehydrated, blocked in BSA con- bedded in paraffin. For immunofluorescence, tissue sections were taining PBS, and sequentially incubated with specific primary rehydrated, blocked in normal donkey serum containing PBS/ antibodies and with biotinylated secondary antibodies (DAKO). 0.2% tween-20, and incubated with specific primary antibodies Streptavidin-peroxidase (DAKO) or Powervision Poly-HRP (Leica and with Alexa Fluor-coupled secondary antibodies. Paraffin Microsystems) was used for visualization and diaminoben- sections were stained with the following primary antibodies: goat zidine as a chromagen (DAKO). The following antibodies were anti-CC10 (1:200; Santa Cruz: sc-9972) and rabbit anti–pro-SPC used: anti-Clara cell antigen 10 (CC10) (goat polyclonal, 1:5,000), (1:1,000; Chemicon; AB3786). Alexa Fluor-coupled secondary anti-high mobility group AT-hook 2 (Hmga2) (rabbit polyclonal, antibodies (Invitrogen) were used at a 1:200 dilution. Images 1:1,000, BioCheck: 59170AP), anti-NK2 homeobox 1 (Nkx2-1) were captured on a Leica SP5C Spectral Confocal Laser Scan- (mouse monoclonal, 1:1,000), anti–pro-Surfactant Protein C ning Microscope. -
A Defined Culture Method Enabling the Establishment of Ring Sideroblasts
LETTERS TO THE EDITOR Table 1. Hematologic and biochemical data. A defined culture method enabling the Hematological data Normal range establishment of ring sideroblasts from induced pluripotent cells of X-linked sideroblastic anemia White blood cells 3,800/µL (4,000 - 9,000) Neutrophils 34% (28 - 68) Congenital sideroblastic anemia is an inherited anemia Lymphocytes 57% (17 - 57) characterized by the presence of bone marrow ring sider- oblasts.1 To date, several causative genes, mostly related to Monocytes 4% (0 - 10) iron and heme metabolism in erythroid cells, have been Eosinophils 4% (0 - 10) 1 considered critical for the formation of ring sideroblasts. Basophils 1% (0 - 2) However, the biological characteristics of ring sideroblasts Red blood cells 450 x 104/ L (427 - 570 x 104) remain elusive because of the lack of an experimental µ model. We established culture conditions to induce ring Hemoglobin 8.1 g/dL (14 - 18) sideroblasts in vitro based on induced pluripotent stem (iPS) Mean corpuscular volume 57.7 fL (80 - 100) cells derived from a patient with congenital sideroblastic Mean corpuscular hemoglobin 31.1% (31 - 35) anemia. To our knowledge, this is the first successful estab- lishment of ring sideroblasts. concentration X-linked sideroblastic anemia (XLSA), the most common Reticulocyte 2.2% (0.7 - 2) type of congenital sideroblastic anemia, is caused by Platelets 60.1 x 104// L (15 - 35 x 104) defects in the X-linked gene encoding 5-aminolevulinic µ 1,2 acid synthase 2 (ALAS2). Most XLSA-associated muta- Biochemical data Normal range tions in ALAS2 are missense substitutions that cause the loss of protein function, whereas mutations in the ALAS2 Total protein 6.9 g/dL (6.7-8.1) regulatory region, which includes the promoter and intron Albumin 4.3 g/dL (3.8-5.3) 1,1 cause decreased ALAS2 expression.