Open chromatin dynamics reveals stage-specific transcriptional networks in hiPSC-based neurodevelopmental model.

Chromatin accessibility to transcription factors (TFs) strongly influences gene transcription and cell differentiation. However, a mechanistic understanding of the transcriptional control during the neuronal differentiation of human induced pluripotent stem cells (hiPSCs), a promising cellular model for mental disorders, remains elusive. Here, we carried out additional analyses on our recently published open chromatin regions (OCRs) profiling at different stages of hiPSC neuronal differentiation. We found that the dynamic changes of OCR during neuronal differentiation highlighted cell stage-specific gene networks, and the chromatin accessibility at the core promoter region of a gene correlates with the corresponding transcript abundance. Within the cell stage-specific OCRs, we identified the binding of cell stage-specific TFs and observed a lag of a neuronal TF binding behind the mRNA expression of the corresponding TF. Interestingly, binding footprints of NEUROD1 and NEUROG2, both of which induce high efficient conversion of hiPSCs to glutamatergic neurons, were among those most enriched in the relatively mature neurons. Furthermore, TF network analysis showed that both NEUROD1 and NEUROG2 were present in the same core TF network specific to more mature neurons, suggesting a pivotal mechanism of epigenetic control of neuronal differentiation and maturation. Our study provides novel insights into the epigenetic control of glutamatergic neurogenesis in the context of TF networks, which may be instrumental to improving hiPSC modeling of neuropsychiatric disorders.