An Activating STAT3 Mutation Causes Neonatal Diabetes through Premature Induction of Pancreatic Differentiation
| Autor: | Salla Keskitalo, Amrinder Malhi, Matias Kinnunen, Solja Eurola, Cristina Valensisi, Mark Russell, Timo Otonkoski, Heli Grym, Jarkko Ustinov, Markku Varjosalo, Noel G. Morgan, Kirmo Wartiovaara, Olli Silvennoinen, Jonna Saarimäki-Vire, R. David Hawkins, Diego Balboa, Colin Andrus, Juha Saarikettu |
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| Přispěvatelé: | Research Programs Unit, Research Programme for Molecular Neurology, Institute of Biotechnology, HUSLAB, Clinicum, Molecular Systems Biology, Timo Pyry Juhani Otonkoski / Principal Investigator, Children's Hospital, Lastentautien yksikkö, HUS Children and Adolescents |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Cellular differentiation Autoimmunity medicine.disease_cause Neonatal diabetes mellitus Insulin-Secreting Cells Basic Helix-Loop-Helix Transcription Factors Insulin Promoter Regions Genetic Induced pluripotent stem cell lcsh:QH301-705.5 Mutation Gene Expression Regulation Developmental Cell Differentiation ENDOCRINE PANCREAS Stem cell Beta cell PLURIPOTENT STEM-CELLS NEUROGENIN3 STAT3 Transcription Factor EXPRESSION medicine.medical_specialty endocrine system Induced Pluripotent Stem Cells Nerve Tissue Proteins Biology General Biochemistry Genetics and Molecular Biology Cell Line 03 medical and health sciences Germline mutation Downregulation and upregulation Internal medicine REVEALS Diabetes Mellitus medicine Humans BETA-LIKE CELLS IN-VITRO Glucagon medicine.disease 030104 developmental biology Endocrinology PROGENITOR CELLS lcsh:Biology (General) Cancer research 1182 Biochemistry cell and molecular biology 3111 Biomedicine CRISPR-Cas Systems KNOCKOUT MICE GENERATION |
| Zdroj: | Cell Reports, Vol 19, Iss 2, Pp 281-294 (2017) |
| ISSN: | 2211-1247 |
| Popis: | Summary: Activating germline mutations in STAT3 were recently identified as a cause of neonatal diabetes mellitus associated with beta-cell autoimmunity. We have investigated the effect of an activating mutation, STAT3K392R, on pancreatic development using induced pluripotent stem cells (iPSCs) derived from a patient with neonatal diabetes and pancreatic hypoplasia. Early pancreatic endoderm differentiated similarly from STAT3K392R and healthy-control cells, but in later stages, NEUROG3 expression was upregulated prematurely in STAT3K392R cells together with insulin (INS) and glucagon (GCG). RNA sequencing (RNA-seq) showed robust NEUROG3 downstream targets upregulation. STAT3 mutation correction with CRISPR/Cas9 reversed completely the disease phenotype. STAT3K392R-activating properties were not explained fully by altered DNA-binding affinity or increased phosphorylation. Instead, reporter assays demonstrated NEUROG3 promoter activation by STAT3 in pancreatic cells. Furthermore, proteomic and immunocytochemical analyses revealed increased nuclear translocation of STAT3K392R. Collectively, our results demonstrate that the STAT3K392R mutation causes premature endocrine differentiation through direct induction of NEUROG3 expression. : Saarimäki-Vire et al. use iPSCs derived from a patient with permanent neonatal diabetes to demonstrate that an activating STAT3 mutation leads to premature NEUROG3 expression and concomitant differentiation of pancreatic progenitors through increased nuclear shuttling of the mutant protein. Keywords: monogenic diabetes, STAT3, NEUROG3, iPSC, stem cells, CRISPR, genome editing, pancreatic differentiation, beta cell, endocrine cells |
| Databáze: | OpenAIRE |
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