Details
- Autor(en) / Beteiligte
- Titel
- Genome Editing of Lineage Determinants in Human Pluripotent Stem Cells Reveals Mechanisms of Pancreatic Development and Diabetes
- Ist Teil von
- Cell stem cell, 2016-06, Vol.18 (6), p.755-768
- Ort / Verlag
- United States: Elsevier Inc
- Erscheinungsjahr
- 2016
- Link zum Volltext
- Quelle
- Elsevier ScienceDirect Journals Complete
- Beschreibungen/Notizen
- Directed differentiation of human pluripotent stem cells (hPSCs) into somatic counterparts is a valuable tool for studying disease. However, examination of developmental mechanisms in hPSCs remains challenging given complex multi-factorial actions at different stages. Here, we used TALEN and CRISPR/Cas-mediated gene editing and hPSC-directed differentiation for a systematic analysis of the roles of eight pancreatic transcription factors (PDX1, RFX6, PTF1A, GLIS3, MNX1, NGN3, HES1, and ARX). Our analysis not only verified conserved gene requirements between mice and humans but also revealed a number of previously unsuspected developmental mechanisms with implications for type 2 diabetes. These include a role of RFX6 in regulating the number of pancreatic progenitors, a haploinsufficient requirement for PDX1 in pancreatic β cell differentiation, and a potentially divergent role of NGN3 in humans and mice. Our findings support use of systematic genome editing in hPSCs as a strategy for understanding mechanisms underlying congenital disorders. [Display omitted] •Genome editing to study pancreatic lineage determinants in hPSC differentiation•A haploinsufficient requirement for PDX1 in pancreatic β cell differentiation•Requirements for RFX6 in pancreatic progenitor and endocrine cell differentiation•Requirements for NGN3 in the formation of glucose-responsive β cells By combining genome editing and hPSC-directed differentiation, Zhu and colleagues systematically examined eight transcription factors for their roles in pancreatic development. Their study not only verified conserved gene requirements between mice and humans but also revealed a number of previously unsuspected and potentially human-specific features.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1934-5909eISSN: 1875-9777DOI: 10.1016/j.stem.2016.03.015Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4892994
- Format
- –
- Schlagworte
- Base Sequence, Basic Helix-Loop-Helix Transcription Factors - metabolism, Cell Differentiation - drug effects, Cell Line, Cell Lineage - drug effects, Cell Lineage - genetics, CRISPR-Cas Systems - genetics, Diabetes Mellitus - pathology, Gene Editing, Gene Knockout Techniques, Genome, Human, Glucose - pharmacology, Haploinsufficiency - drug effects, Homeodomain Proteins - metabolism, Human Embryonic Stem Cells - cytology, Human Embryonic Stem Cells - drug effects, Human Embryonic Stem Cells - metabolism, Humans, Infant, Newborn, Insulin-Secreting Cells - drug effects, Insulin-Secreting Cells - metabolism, Insulin-Secreting Cells - pathology, Mutation - genetics, Nerve Tissue Proteins - metabolism, Pancreas - embryology, Pancreas - pathology, Phenotype, Pluripotent Stem Cells - cytology, Pluripotent Stem Cells - drug effects, Pluripotent Stem Cells - metabolism, Regulatory Factor X Transcription Factors - metabolism, Time Factors, Trans-Activators - metabolism