Project description:During gestation, alveolar cells are derived from luminal progenitors in the mammary gland. However, the mechanism underlying luminal progenitor commitment to alveolar cells remains largely unknown. By using five genetically modified mouse lines and single cell RNA sequencing, we identified a Kindlin-2 - Stat3 - Dll1 signaling cascade in myoepithelial cells which controls the inactivation of Notch signaling in luminal cells that consequently drives luminal progenitor commitment to alveolar cells. We found that loss of Kindlin-2 in myoepithelial cells impairs mammary morphogenesis and alveologenesis, and lactation. Single-cell profiling reveals that Kindlin-2 loss significantly decreases the proportion of alveolar cells.
Project description:Here we describe the application of high-throughput sequencing technology for profiling histone and DNA methylation, and gene expression patterns of normal human mammary progenitor-enriched and luminal lineage-committed cells. We observed significant differences in histone H3 lysine 27 tri-methylation (H3K27me3) enrichment and DNA methylation of genes expressed in a cell type-specific manner, suggesting their regulation by epigenetic mechanisms and a dynamic interplay between the two processes that together define developmental potential. The technologies we developed and the epigenetically regulated genes we identified will accelerate the characterization of primary cell epigenomes and the dissection of human mammary epithelial lineage-commitment and luminal differentiation. Global profiling of differentially methylated regions in 2 cell types from 6 individuals.
Project description:Here we describe the application of high-throughput sequencing technology for profiling histone and DNA methylation, and gene expression patterns of normal human mammary progenitor-enriched and luminal lineage-committed cells. We observed significant differences in histone H3 lysine 27 tri-methylation (H3K27me3) enrichment and DNA methylation of genes expressed in a cell type-specific manner, suggesting their regulation by epigenetic mechanisms and a dynamic interplay between the two processes that together define developmental potential. The technologies we developed and the epigenetically regulated genes we identified will accelerate the characterization of primary cell epigenomes and the dissection of human mammary epithelial lineage-commitment and luminal differentiation. Examination of histone H3K27me3 modifications in 2 cell types from 3 individuals and H3K4me3 modifications in 2 cell types from one individual sample.
