The gene regulatory landscape during human inhibitory interneuron differentiation

Cortical Interneurons, despite being a minority cell population, play an important role in brain development and are critical for proper cortical function. Cortical interneurons (INs) originate in the medial ganglionic eminence (MGE) of the developing brain, from which, they migrate and differentiate into mature INs in the cortex. During migration and further neural circuit integration, INs acquire distinguishing mature characteristics attributable to different neuronal subtypes. This process is controlled by hierarchical and tightly regulated gene expression profiles. However, the expression regulation of this process is not well understood. Here, we characterized the regulatory landscape and determined the transcription factors, enhancers and their corresponding target genes that are required for executing the expression profiles during INs differentiation. Using ChIP-seq, ATAC-seq, RNA-seq, we identified potential regulatory elements during human stem cell differentiated into IN-like progenitors. Using genome architecture mapping (GAM) assay, high resolution genome interaction maps were generated and cross-referenced with enhancer epigenetic markers and expression data to identify potential enhancer-promoter interactions during IN-like differentiation. We found that our regulatory landscape supports the regulation of transcription factors and enhancer elements that are known to be involved in IN differentiation. Combined, this study generated a compressive regulatory map of IN-like cells during normal brain development. Moreover, these maps can be used to screen for non-coding regulatory mutations in patients with neurodevelopmental disorders whom no protein coding mutations were found.