Clonal Analysis Delineates Transcriptional Programs of Osteogenic and Adipogenic Lineages of Adult Mouse Skeletal Progenitors

Summary: Bone, cartilage, and marrow adipocytes are generated by skeletal progenitors, but the relationships between lineages and mechanisms controlling their differentiation are poorly understood. We established mouse clonal skeletal progenitors with distinct differentiation properties and analyzed their transcriptome. Unipotent osteogenic and adipogenic cells expressed specific transcriptional programs, whereas bipotent clones combined expression of those genes and did not show a unique signature. We tested potential regulators of lineage commitment and found that in the presence of interferon-γ (IFNγ) adipogenic clones can be induced to osteogenesis and that their adipogenic capacity is inhibited. Analysis of IFNγ-regulated genes showed that lineage signatures and fate commitment of skeletal progenitors were controlled by EGR1 and EGR2. Knockdown experiments revealed that EGR1 is a positive regulator of the adipogenic transcriptional program and differentiation capacity, whereas EGR2 inhibits the osteogenic program and potency. Therefore, our work revealed transcriptional signatures of osteogenic and adipogenic lineages and mechanism triggering cell fate. : In this article, Rostovskaya and colleagues established clonal skeletal progenitors with distinct differentiation properties from mouse bone marrow. RNA-seq analysis revealed transcriptional signatures of osteogenic and adipogenic lineages and IFNγ signaling as potential regulator of cell fate commitment. IFNγ is a negative regulator of Egr1 and Egr2 transcription factors. Egr1 maintains adipogenic and Egr2 suppresses osteogenic transcriptional program and commitment. Keywords: bone marrow stromal cells, skeletal progenitors, lineage commitment, transcriptional signatures, interferon-γ signaling, Egr1/2 transcription factor