Lineage-selective super enhancers mediate core regulatory circuitry during adipogenic and osteogenic differentiation of human mesenchymal stem cells

Human mesenchymal stem cells (hMSCs) can be differentiated into osteoblasts and adipocytes. During these processes, super enhancers (SEs) play important roles. Here, we performed comprehensive characterization of the SEs changes associated with adipogenic and osteogenic differentiation of hMSCs, and revealed that SEs changed more dramatically compared with typical enhancers. We identified a set of lineage-selective SEs, whose target genes were enriched with cell type-specific functions. Functional experiments in lineage-selective SEs demonstrated their specific roles in directed differentiation of hMSCs. We also found that some key transcription factors regulated by lineage-selective SEs could form core regulatory circuitry (CRC) to regulate each other's expression and control the hMSCs fate determination. In addition, we found that GWAS SNPs of osteoporosis and obesity were significantly enriched in osteoblasts-selective SEs or adipocytes-selective SEs, respectively. Taken together, our studies unveiled important roles of lineage-selective SEs in hMSCs differentiation into osteoblasts and adipocytes.

Automated summary

This study comprehensively characterized the changes in super enhancers (SEs) during the differentiation of human mesenchymal stem cells (hMSCs) into osteoblasts and adipocytes, revealing that SEs undergo more dramatic changes compared to typical enhancers. Lineage-selective SEs were identified and found to play specific roles in the directed differentiation of hMSCs. Additionally, key transcription factors regulated by lineage-selective SEs were shown to form a core regulatory circuitry that controls the fate determination of hMSCs. Furthermore, GWAS SNPs associated with osteoporosis and obesity were found to be significantly enriched in osteoblasts-selective SEs and adipocytes-selective SEs, respectively.