UC San Diego

RE1-Silencing Transcription Factor (REST), a member of the Kruppel-type zinc finger transcription factor family, is believed to act as a master negative regulator of neurogenesis. During neurogenesis, the decreasing expression of REST leads to increased expression of neuronal genes and the emergence of neuronal processes over time. The temporal patterns of REST-controlled processes and transcriptional regulatory events underlying neural induction and early neural development have not been studied utilizing a systems-level approach on high-throughput time course data.

Human-derived induced Pluripotent Stem Cells (iPSCs) combined with well-established neural differentiation protocols allow for the in-vitro elucidation of gene expression patterns characteristic of human neurodevelopment during this crucial early in-vivo developmental phase.

Using time series data capturing genome-wide transcriptome information from human iPSCs differentiating into i) Cortical and ii) Hypothalamic neurons, REST-controlled gene regulatory networks (GRNs) were generated. These GRNs captured transcription factor-target regulatory interactions across the time series and were investigated in order to elucidate early neurodevelopment towards the two neuronal phenotypes. Functional enrichment analysis of gene sets obtained from these GRNs was used to determine where along the time series different REST-controlled neuronal processes emerged.

The systems-level approach allowed for temporal resolution of genome-wide trans-regulatory interactions over the time course, the dynamics of which underlie neural differentiation and development. The outcome of the research is a novel qualitative kinetic model consisting of the time-varying GRNs under the control of REST that gives insight into the i) temporal sequence of emergent neuronal processes accompanying neurodifferentiation and ii) the temporal sequence of key transcriptional regulatory events underlying the early neural differentiation of hiPSCs.