Molecular Characterization of Down Syndrome Embryonic Stem Cells Reveals a Role for RUNX1 in Neural Differentiation.
Down syndrome (DS) is the leading genetic cause of mental retardation and is caused by a third copy of human chromosome 21. The different pathologies of DS involve many tissues with a distinct array of neural phenotypes. Here we characterize embryonic stem cell lines with DS (DS-ESCs), and focus on the neural aspects of the disease. Our results show that neural progenitor cells (NPCs) differentiated from five independent DS-ESC lines display increased apoptosis and downregulation of forehead developmental genes. Analysis of differentially expressed genes suggested RUNX1 as a key transcription regulator in DS-NPCs. Using genome editing we were able to disrupt all three copies of RUNX1 in DS-ESCs, leading to downregulation of several RUNX1 target developmental genes accompanied by reduced apoptosis and neuron migration. Our work sheds light on the role of RUNX1 and the importance of dosage balance in the development of neural phenotypes in DS.
Department of Genetics, The Azrieli Center for Stem Cells and Genetic Research, Institute of Life Sciences, The Hebrew University, Givat-Ram, Jerusalem 91904, Israel.
Tomer
T
Halevy
Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA 90048, USA.
Juan-Carlos
JC
Biancotti
Department of Genetics, The Azrieli Center for Stem Cells and Genetic Research, Institute of Life Sciences, The Hebrew University, Givat-Ram, Jerusalem 91904, Israel.
Ofra
O
Yanuka
Department of Genetics, The Azrieli Center for Stem Cells and Genetic Research, Institute of Life Sciences, The Hebrew University, Givat-Ram, Jerusalem 91904, Israel.
Tamar
T
Golan-Lev
Department of Genetics, The Azrieli Center for Stem Cells and Genetic Research, Institute of Life Sciences, The Hebrew University, Givat-Ram, Jerusalem 91904, Israel. Electronic address: nissimb@mail.huji.ac.il.
Nissim
N
Benvenisty
D017209:Apoptosis / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D002478:Cells, Cultured; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics* / Q000378:metabolism; D004314:Down Syndrome / Q000235:genetics* / Q000378:metabolism*; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D018628:Gene Dosage; D000072669:Gene Editing; D006801:Humans; D059785:Karyotype; D058953:Neural Stem Cells / Q000166:cytology* / Q000378:metabolism*; D055495:Neurogenesis / Q000235:genetics; D010641:Phenotype
D050676:Core Binding Factor Alpha 2 Subunit