Global Reorganisation of Cis-Regulatory Units Upon Lineage
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The Transcription Factor Pou3f1 Promotes Neural Fate Commitment
RESEARCH ARTICLE elifesciences.org The transcription factor Pou3f1 promotes neural fate commitment via activation of neural lineage genes and inhibition of external signaling pathways Qingqing Zhu1,2†, Lu Song1†, Guangdun Peng1, Na Sun3, Jun Chen1, Ting Zhang1, Nengyin Sheng1, Wei Tang1, Cheng Qian1, Yunbo Qiao1, Ke Tang4, Jing-Dong Jackie Han3, Jinsong Li1, Naihe Jing1* 1State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; 2Department of Neurosurgery, West China Hospital, Sichuan University, Sichuan, China; 3Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; 4Institute of Life Science, Nanchang University, Nanchang, Jiangxi, China Abstract The neural fate commitment of pluripotent stem cells requires the repression of extrinsic inhibitory signals and the activation of intrinsic positive transcription factors. However, how these two events are integrated to ensure appropriate neural conversion remains unclear. In this study, we showed that Pou3f1 is essential for the neural differentiation of mouse embryonic stem cells (ESCs), specifically during the transition from epiblast stem cells (EpiSCs) to neural progenitor cells (NPCs). Chimeric analysis showed that Pou3f1 knockdown leads to a markedly decreased *For correspondence: njing@ incorporation of ESCs in the neuroectoderm. By contrast, Pou3f1-overexpressing ESC derivatives sibcb.ac.cn preferentially contribute to the neuroectoderm. Genome-wide ChIP-seq and RNA-seq analyses †These authors contributed indicated that Pou3f1 is an upstream activator of neural lineage genes, and also is a repressor of equally to this work BMP and Wnt signaling. -
In Vivo Studies Using the Classical Mouse Diversity Panel
The Mouse Diversity Panel Predicts Clinical Drug Toxicity Risk Where Classical Models Fail Alison Harrill, Ph.D The Hamner-UNC Institute for Drug Safety Sciences 0 The Importance of Predicting Clinical Adverse Drug Reactions (ADR) Figure: Cath O’Driscoll Nature Publishing 2004 Risk ID PGx Testing 1 People Respond Differently to Drugs Pharmacogenetic Markers Identified by Genome-Wide Association Drug Adverse Drug Risk Allele Reaction (ADR) Abacavir Hypersensitivity HLA-B*5701 Flucloxacillin Hepatotoxicity Allopurinol Cutaneous ADR HLA-B*5801 Carbamazepine Stevens-Johnson HLA-B*1502 Syndrome Augmentin Hepatotoxicity DRB1*1501 Ximelagatran Hepatotoxicity DRB1*0701 Ticlopidine Hepatotoxicity HLA-A*3303 Average preclinical populations and human hepatocytes lack the diversity to detect incidence of adverse events that occur only in 1/10,000 people. Current Rodent Models of Risk Assessment The Challenge “At a time of extraordinary scientific progress, methods have hardly changed in several decades ([FDA] 2004)… Toxicologists face a major challenge in the twenty-first century. They need to embrace the new “omics” techniques and ensure that they are using the most appropriate animals if their discipline is to become a more effective tool in drug development.” -Dr. Michael Festing Quantitative geneticist Toxicol Pathol. 2010;38(5):681-90 Rodent Models as a Strategy for Hazard Characterization and Pharmacogenetics Genetically defined rodent models may provide ability to: 1. Improve preclinical prediction of drugs that carry a human safety risk 2. -
TFEB Regulates Murine Liver Cell Fate During Development and Regeneration ✉ Nunzia Pastore 1,2 , Tuong Huynh1,2, Niculin J
ARTICLE https://doi.org/10.1038/s41467-020-16300-x OPEN TFEB regulates murine liver cell fate during development and regeneration ✉ Nunzia Pastore 1,2 , Tuong Huynh1,2, Niculin J. Herz1,2, Alessia Calcagni’ 1,2, Tiemo J. Klisch1,2, Lorenzo Brunetti 3,4, Kangho Ho Kim5, Marco De Giorgi6, Ayrea Hurley6, Annamaria Carissimo7, Margherita Mutarelli7, Niya Aleksieva 8, Luca D’Orsi7, William R. Lagor6, David D. Moore 5, ✉ Carmine Settembre7,9, Milton J. Finegold10, Stuart J. Forbes8 & Andrea Ballabio 1,2,7,9 1234567890():,; It is well established that pluripotent stem cells in fetal and postnatal liver (LPCs) can differentiate into both hepatocytes and cholangiocytes. However, the signaling pathways implicated in the differentiation of LPCs are still incompletely understood. Transcription Factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy, is known to be involved in osteoblast and myeloid differentiation, but its role in lineage commitment in the liver has not been investigated. Here we show that during development and upon regen- eration TFEB drives the differentiation status of murine LPCs into the progenitor/cho- langiocyte lineage while inhibiting hepatocyte differentiation. Genetic interaction studies show that Sox9, a marker of precursor and biliary cells, is a direct transcriptional target of TFEB and a primary mediator of its effects on liver cell fate. In summary, our findings identify an unexplored pathway that controls liver cell lineage commitment and whose dysregulation may play a role in biliary cancer. 1 Jan and Dan Duncan Neurological Research Institute, Texas Children Hospital, Houston, TX 77030, USA. 2 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. -
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. -
Effects of Activation of the LINE-1 Antisense Promoter on the Growth of Cultured Cells
www.nature.com/scientificreports OPEN Efects of activation of the LINE‑1 antisense promoter on the growth of cultured cells Tomoyuki Honda1*, Yuki Nishikawa1, Kensuke Nishimura1, Da Teng1, Keiko Takemoto2 & Keiji Ueda1 Long interspersed element 1 (LINE‑1, or L1) is a retrotransposon that constitutes ~ 17% of the human genome. Although ~ 6000 full‑length L1s spread throughout the human genome, their biological signifcance remains undetermined. The L1 5′ untranslated region has bidirectional promoter activity with a sense promoter driving L1 mRNA production and an antisense promoter (ASP) driving the production of L1‑gene chimeric RNAs. Here, we stimulated L1 ASP activity using CRISPR‑Cas9 technology to evaluate its biological impacts. Activation of the L1 ASP upregulated the expression of L1 ASP‑driven ORF0 and enhanced cell growth. Furthermore, the exogenous expression of ORF0 also enhanced cell growth. These results indicate that activation of L1 ASP activity fuels cell growth at least through ORF0 expression. To our knowledge, this is the frst report demonstrating the role of the L1 ASP in a biological context. Considering that L1 sequences are desilenced in various tumor cells, our results indicate that activation of the L1 ASP may be a cause of tumor growth; therefore, interfering with L1 ASP activity may be a potential strategy to suppress the growth. Te human genome contains many transposable element-derived sequences, such as endogenous retroviruses and long interspersed element 1 (LINE-1, or L1). L1 is one of the major classes of retrotransposons, and it constitutes ~ 17% of the human genome1. Full-length L1 consists of a 5′ untranslated region (UTR), two open reading frames (ORFs) that encode the proteins ORF1p and ORF2p, and a 3′ UTR with a polyadenylation signal. -
Full-Length Cdna, Expression Pattern and Association Analysis of the Porcine FHL3 Gene
1473 Asian-Aust. J. Anim. Sci. Vol. 20, No. 10 : 1473 - 1477 October 2007 www.ajas.info Full-length cDNA, Expression Pattern and Association Analysis of the Porcine FHL3 Gene Bo Zuo*, YuanZhu Xiong, Hua Yang and Jun Wang Key Laboratory of Swine Genetics and Breeding, Ministry of Agriculture & Key Lab of Agricultural Animal Genetics, Breeding and Reproduction, Ministry of Education, College of Animal Science and Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, P. R. China ABSTRACT : Four-and-a-half LIM-only protein 3 (FHL3) is a member of the LIM protein superfamily and can participate in mediating protein-protein interaction by binding one another through their LIM domains. In this study, the 5'- and 3'- cDNA ends were characterized by RACE (Rapid Amplification of the cDNA Ends) methodology in combination with in silica cloning based on the partial cDNA sequence obtained. Bioinformatics analysis showed FHL3 protein contained four LIM domains and four LIM zinc-binding domains. In silica mapping assigned this gene to the gene cluster MTF1-INPP5B-SF3A3-FHL3-CGI-94 on pig chromosome 6 where several QTL affecting intramuscular fat and eye muscle area had previously been identified. Transcription of the FHL3 gene was detected in spleen, liver, kidney, small intestine, skeletal muscle, fat and stomach, with the greatest expression in skeletal muscle. The A/G polymorphism in exon II was significantly associated with birth weight, average daily gain before weaning, drip loss rate, water holding capacity and intramuscular fat in a Landrace-derived pig population. Together, the present study provided the useful information for further studies to determine the roles of FHL3 gene in the regulation of skeletal muscle cell growth and differentiation in pigs. -
The for Report 07-08
THE CENTER FOR INTEGRATIVE GENOMICS REPORT 07-08 www.unil.ch/cig Table of Contents INTRODUCTION 2 The CIG at a glance 2 The CIG Scientific Advisory Committee 3 Message from the Director 4 RESEARCH 6 Richard Benton Chemosensory perception in Drosophila: from genes to behaviour 8 Béatrice Desvergne Networking activity of PPARs during development and in adult metabolic homeostasis 10 Christian Fankhauser The effects of light on plant growth and development 12 Paul Franken Genetics and energetics of sleep homeostasis and circadian rhythms 14 Nouria Hernandez Mechanisms of basal and regulated RNA polymerase II and III transcription of ncRNA in mammalian cells 16 Winship Herr Regulation of cell proliferation 18 Henrik Kaessmann Mammalian evolutionary genomics 20 Sophie Martin Molecular mechanisms of cell polarization 22 Liliane Michalik Transcriptional control of tissue repair and angiogenesis 24 Alexandre Reymond Genome structure and expression 26 Andrzej Stasiak Functional transitions of DNA structure 28 Mehdi Tafti Genetics of sleep and the sleep EEG 30 Bernard Thorens Molecular and physiological analysis of energy homeostasis in health and disease 32 Walter Wahli The multifaceted roles of PPARs 34 Other groups at the Génopode 37 CORE FACILITIES 40 Lausanne DNA Array Facility (DAFL) 42 Protein Analysis Facility (PAF) 44 Core facilities associated with the CIG 46 EDUCATION 48 Courses and lectures given by CIG members 50 Doing a PhD at the CIG 52 Seminars and symposia 54 The CIG annual retreat 62 The CIG and the public 63 Artist in residence at the CIG 63 PEOPLE 64 1 Introduction The Center for IntegratiVE Genomics (CIG) at A glance The Center for Integrative Genomics (CIG) is the newest depart- ment of the Faculty of Biology and Medicine of the University of Lausanne (UNIL). -
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). -
Integrating Single-Step GWAS and Bipartite Networks Reconstruction Provides Novel Insights Into Yearling Weight and Carcass Traits in Hanwoo Beef Cattle
animals Article Integrating Single-Step GWAS and Bipartite Networks Reconstruction Provides Novel Insights into Yearling Weight and Carcass Traits in Hanwoo Beef Cattle Masoumeh Naserkheil 1 , Abolfazl Bahrami 1 , Deukhwan Lee 2,* and Hossein Mehrban 3 1 Department of Animal Science, University College of Agriculture and Natural Resources, University of Tehran, Karaj 77871-31587, Iran; [email protected] (M.N.); [email protected] (A.B.) 2 Department of Animal Life and Environment Sciences, Hankyong National University, Jungang-ro 327, Anseong-si, Gyeonggi-do 17579, Korea 3 Department of Animal Science, Shahrekord University, Shahrekord 88186-34141, Iran; [email protected] * Correspondence: [email protected]; Tel.: +82-31-670-5091 Received: 25 August 2020; Accepted: 6 October 2020; Published: 9 October 2020 Simple Summary: Hanwoo is an indigenous cattle breed in Korea and popular for meat production owing to its rapid growth and high-quality meat. Its yearling weight and carcass traits (backfat thickness, carcass weight, eye muscle area, and marbling score) are economically important for the selection of young and proven bulls. In recent decades, the advent of high throughput genotyping technologies has made it possible to perform genome-wide association studies (GWAS) for the detection of genomic regions associated with traits of economic interest in different species. In this study, we conducted a weighted single-step genome-wide association study which combines all genotypes, phenotypes and pedigree data in one step (ssGBLUP). It allows for the use of all SNPs simultaneously along with all phenotypes from genotyped and ungenotyped animals. Our results revealed 33 relevant genomic regions related to the traits of interest. -
Dynamic Transcriptomic Profiles of Zebrafish Gills in Response to Zinc
Zheng et al. BMC Genomics 2010, 11:548 http://www.biomedcentral.com/1471-2164/11/548 RESEARCH ARTICLE Open Access Dynamic transcriptomic profiles of zebrafish gills in response to zinc depletion Dongling Zheng1,4, Peter Kille2, Graham P Feeney2, Phil Cunningham1, Richard D Handy3, Christer Hogstrand1* Abstract Background: Zinc deficiency is detrimental to organisms, highlighting its role as an essential micronutrient contributing to numerous biological processes. To investigate the underlying molecular events invoked by zinc depletion we performed a temporal analysis of transcriptome changes observed within the zebrafish gill. This tissue represents a model system for studying ion absorption across polarised epithelial cells as it provides a major pathway for fish to acquire zinc directly from water whilst sharing a conserved zinc transporting system with mammals. Results: Zebrafish were treated with either zinc-depleted (water = 2.61 μgL-1; diet = 26 mg kg-1) or zinc-adequate (water = 16.3 μgL-1; diet = 233 mg kg-1) conditions for two weeks. Gill samples were collected at five time points and transcriptome changes analysed in quintuplicate using a 16K oligonucleotide array. Of the genes represented the expression of a total of 333 transcripts showed differential regulation by zinc depletion (having a fold-change greater than 1.8 and an adjusted P-value less than 0.1, controlling for a 10% False Discovery Rate). Down-regulation was dominant at most time points and distinct sets of genes were regulated at different stages. Annotation enrichment analysis revealed that ‘Developmental Process’ was the most significantly overrepresented Biological Process GO term (P = 0.0006), involving 26% of all regulated genes. -
Genome-Wide DNA Methylation Analysis of KRAS Mutant Cell Lines Ben Yi Tew1,5, Joel K
www.nature.com/scientificreports OPEN Genome-wide DNA methylation analysis of KRAS mutant cell lines Ben Yi Tew1,5, Joel K. Durand2,5, Kirsten L. Bryant2, Tikvah K. Hayes2, Sen Peng3, Nhan L. Tran4, Gerald C. Gooden1, David N. Buckley1, Channing J. Der2, Albert S. Baldwin2 ✉ & Bodour Salhia1 ✉ Oncogenic RAS mutations are associated with DNA methylation changes that alter gene expression to drive cancer. Recent studies suggest that DNA methylation changes may be stochastic in nature, while other groups propose distinct signaling pathways responsible for aberrant methylation. Better understanding of DNA methylation events associated with oncogenic KRAS expression could enhance therapeutic approaches. Here we analyzed the basal CpG methylation of 11 KRAS-mutant and dependent pancreatic cancer cell lines and observed strikingly similar methylation patterns. KRAS knockdown resulted in unique methylation changes with limited overlap between each cell line. In KRAS-mutant Pa16C pancreatic cancer cells, while KRAS knockdown resulted in over 8,000 diferentially methylated (DM) CpGs, treatment with the ERK1/2-selective inhibitor SCH772984 showed less than 40 DM CpGs, suggesting that ERK is not a broadly active driver of KRAS-associated DNA methylation. KRAS G12V overexpression in an isogenic lung model reveals >50,600 DM CpGs compared to non-transformed controls. In lung and pancreatic cells, gene ontology analyses of DM promoters show an enrichment for genes involved in diferentiation and development. Taken all together, KRAS-mediated DNA methylation are stochastic and independent of canonical downstream efector signaling. These epigenetically altered genes associated with KRAS expression could represent potential therapeutic targets in KRAS-driven cancer. Activating KRAS mutations can be found in nearly 25 percent of all cancers1. -
By Submitted in Partial Satisfaction of the Requirements for Degree of in In
BCL6 maintains thermogenic capacity of brown adipose tissue during dormancy by Vassily Kutyavin DISSERTATION Submitted in partial satisfaction of the requirements for degree of DOCTOR OF PHILOSOPHY in Biomedical Sciences in the GRADUATE DIVISION of the UNIVERSITY OF CALIFORNIA, SAN FRANCISCO Approved: ______________________________________________________________________________Eric Verdin Chair ______________________________________________________________________________Ajay Chawla ______________________________________________________________________________Ethan Weiss ______________________________________________________________________________ ______________________________________________________________________________ Committee Members Copyright 2019 by Vassily Kutyavin ii Dedicated to everyone who has supported me during my scientific education iii Acknowledgements I'm very grateful to my thesis adviser, Ajay Chawla, for his mentorship and support during my dissertation work over the past five years. Throughout my time in his lab, I was always able to rely on his guidance, and his enthusiasm for science was a great source of motivation. Even when he was traveling, he could easily be reached for advice by phone or e- mail. I am particularly grateful for his help with writing the manuscript, which was probably the most challenging aspect of graduate school for me. I am also very grateful to him for helping me find a postdoctoral fellowship position. Ajay's inquisitive and fearless approach to science have been a great inspiration to me. In contrast to the majority of scientists who focus narrowly on a specific topic, Ajay pursued fundamental questions across a broad range of topics and was able to make tremendous contributions. My experience in his lab instilled in me a deep appreciation for thinking about the entire organism from an evolutionary perspective and focusing on the key questions that escape the attention of the larger scientific community. As I move forward in my scientific career, there is no doubt that I will rely on him as a role model.