Integrative genome-scale analyses reveal post-transcriptional signatures of early human small intestinal development in a directed differentiation organoid model
Integrative genome-scale analyses reveal post-transcriptional signatures of early human small intestinal development in a directed differentiation organoid model
Blog Article
Abstract Background MicroRNAs (miRNAs) are important post-transcriptional gene regulators controlling cellular lineage specification and differentiation during Coverage of mass drug administration for elimination of lymphatic filariasis in urban Nagpur, Central India: A mixed method study embryonic development, including the gastrointestinal system.However, miRNA-mediated regulatory mechanisms involved in early embryonic development of human small intestine (SI) remains underexplored.To explore candidate roles for miRNAs in prenatal SI lineage specification in humans, we used a multi-omic analysis strategy in a directed differentiation model that programs human pluripotent stem cells toward the SI lineage.
Results We leveraged small RNA-seq to define the changing miRNA landscape, and integrated chromatin run-on sequencing (ChRO-seq) and RNA-seq to define genes subject to significant post-transcriptional regulation across the different stages of differentiation.Small RNA-seq profiling revealed temporal dynamics of miRNA signatures across different developmental events of the model, including definitive endoderm formation, SI lineage specification and SI regional patterning.Our multi-omic, integrative analyses showed further that the elevation of miR-182 and reduction of miR-375 are key events during SI lineage specification.
We demonstrated that loss of miR-182 leads to an increase in the foregut master marker SOX2.We also used single-cell analyses in murine adult intestinal crypts to support a life-long role for miR-375 in the regulation of Zfp36l2.Finally, we uncovered opposing roles of SMAD4 and WNT signaling in regulating miR-375 expression during SI lineage specification.
Beyond the mechanisms highlighted in this study, we also present a web-based application for exploration of post-transcriptional regulation and miRNA-mediated control in the context of early human SI development.Conclusion The present study uncovers a novel facet of miRNAs in regulating prenatal SI development.We leveraged multi-omic, systems biology approaches to discover candidate miRNA regulators associated with early SI developmental events in a human organoid model.
In this study, we Investigation of Furrow Formation by Rotary Tillage Tools with an Active Drive highlighted miRNA-mediated post-transcriptional regulation relevant to the event of SI lineage specification.The candidate miRNA regulators that we identified for the other stages of SI development also warrant detailed characterization in the future.