Project description:CHARGE syndrome is caused by heterozygous mutations in a chromatin remodeler CHD7 and characterized by a set of malformations historically postulated to arise from defects in the neural crest formation during embryogenesis. To better delineate neural crest defects in CHARGE syndrome, we generated induced pluripotent stem cells (iPSCs) from two patients with typical syndrome manifestations, and characterized neural crest cells differentiated in vitro from these iPSCs (iPSC-NCCs). We found that expression of genes associated with cell migration was altered in CHARGE iPSC-NCCs as compared to control iPSC-NCCs. Consistently, CHARGE iPSC-NCCs showed defective delamination, migration and motility in vitro, and their transplantation in ovo revealed overall defective migratory activity in the chick embryo. Altogether, our results support the historical inference that CHARGE syndrome patients have defects in neural crest migration and provide the first successful application of patient-derived iPSCs in modeling craniofacial disorders.
Project description:We hypothesized that the positive charge of CRP K100 is important for transcription of Class II CRP-dependent genes. These data show mutations that affect K100 charge status result in genome-wide changes in transcription of both CRP-dependent and -independent genes.
