A single-cell multiomic analysis of kidney organoid differentiation

Kidney organoids differentiated from pluripotent stem cells are powerful models of kidney development and disease but are characterized by cell immaturity and off-target cell fates. Comparing the cell-specific gene regulatory landscape during organoid differentiation with human adult kidney can serve to benchmark progress in differentiation at the epigenome and transcriptome level for individual organoid cell types. Using single-cell multiome and histone modification analysis, we report more broadly open chromatin in organoid cell types compared to the human adult kidney. We infer enhancer dynamics by cis-coaccessibility analysis and validate an enhancer driving transcription of HNF1B by CRISPR interference both in cultured proximal tubule cells and also during organoid differentiation. Our approach provides an experimental framework to judge the cell-specific maturation state of human kidney organoids and shows that kidney organoids can be used to validate individual gene regulatory networks that regulate differentiation.

Automated summary

Comparing the gene regulatory landscape between kidney organoids and adult human kidney can help evaluate the differentiation progress at the epigenome and transcriptome level. The study found that organoid cell types have more open chromatin compared to adult human kidney. Using enhancer dynamics analysis, the researchers validated an enhancer that drives transcription of HNF1B during organoid differentiation. This study provides an experimental framework to assess the cell-specific maturation state of human kidney organoids and validates gene regulatory networks involved in differentiation.