Chromatin regulatory dynamics of early development and regional specification in a directed differentiation model of the human small intestine

The appropriate development of the small intestine (SI) is critical for efficient nutrient absorption and barrier function after birth. Most of the molecular features and regional patterning of the SI are programmed very early in prenatal development. However, the chromatin regulatory dynamics that underpin early SI development in humans is largely unknown. To fill this knowledge void, we apply a cutting-edge genomic technology to a state-of-the-art model of human SI development. Specifically, we leverage chromatin run-on sequencing (ChRO-seq) to define the landscape of active transcriptional regulatory elements across early stages of directed differentiation of human pluripotent stem cells (hPSCs) into SI organoids. Through comprehensive bioinformatic analysis of the data we provide the first-ever view of the changing chromatin regulatory landscape and define stage-specific key enhancer hotspots during human SI development. We also identify candidate transcription factors and their cistromes that are associated with the acquisition of SI identity and the initiation of regional patterning. This work offers a rich resource for studying transcriptional regulation of early human SI development.