EOFAD-causing mutations in psen1 orchestrate dedifferentiation through remodeling of the chromatin landscape in hiPSC-derived neurons [ATAC-Seq]

In this work, we used an integrative, multi-omics approach and systems-level analysis to generate a mechanistic disease model for EOFAD in an hiPSC-derived neuron model system. Overall design: hiPSC-derived neurons were generated from patient-specific Non-Demented Control, PSEN1M146L, PSEN1H163R, PSEN1A246E, and PSEN1A431E fibroblasts and subjected to RNA-Seq, ATAC-Seq, and histone methylation ChiP-Seq. For ATAC-Seq, transposition experiments were performed as previously reported on 50,000 NDC (n = 5), PSEN1M146L (n = 2), PSEN1H163R (n = 3), PSEN1A246E (n = 2), and PSEN1A431E (n = 3) hiPSC-derived neuron cells using the Illumina Nextera DNA Sample Preperation kit and Qiagen MinElute PCR Purification kit. ATAC-Seq libraries were generated from transposed DNA using the Kapa Biosystems Real-Time Library Amplification kit and further purified using the Qiagen MinElute PCR Purification kit; sequencing was performed an Illumina HiSeq4000 platform generating Paired-End, 50bp reads with an average of 25 million reads per sample.