PLX075014

GSE109524: Genome-scale Screens Uncover JNK/JUN signaling as a Key Barrier from Pluripotency to Human Endoderm Differentiation

• Organsim human
• Type RNASEQ
• Target gene
• Project ARCHS4

Human embryonic stem cells (hESCs) are uniquely suitable for interrogating human development and birth defects with high-throughput genetic manipulation. Using CRISPR/Cas, we have conducted a forward genetic screen for genes that regulate the differentiation of human definitive endoderm (DE), the first step towards the generation of cells in respiratory and gastrointestinal organs. Our screen identified both known and unknown regulators of endoderm differentiation, including a previously unrecognized inhibitory mechanism mediated by the JNK/JUN pathway. JNK inhibitor treatment significantly improves the efficiency of hESC differentiation to endoderm and endoderm-derived pancreatic and lung lineage cells. Genome-wide analysis shows that the AP1 transcription factor JUN co-occupies ESC enhancers with SMAD2/3 and OCT4, and impedes the decommissioning of ESC enhancers during DE differentiation. JNK inhibition promotes DE differentiation through accelerating the reconfiguration of the SMAD2/3 chromatin-binding from ESC to DE enhancers. Our screen discovered a new mechanism regulating DE differentiation and establishes a framework for unbiased interrogation of the functional genome during hESC differentiation and human development. SOURCE: QINGL LI MEMORIAL SLOAN KETTERING CANCER CENTER