| First Author | Johnson KD | Year | 2020 |
| Journal | J Exp Med | Volume | 217 |
| Issue | 11 | PubMed ID | 32736380 |
| Mgi Jnum | J:357068 | Mgi Id | MGI:6477217 |
| Doi | 10.1084/jem.20191526 | Citation | Johnson KD, et al. (2020) Constructing and deconstructing GATA2-regulated cell fate programs to establish developmental trajectories. J Exp Med 217(11) |
| abstractText | Stem and progenitor cell fate transitions constitute key decision points in organismal development that enable access to a developmental path or actively preclude others. Using the hematopoietic system, we analyzed the relative importance of cell fate-promoting mechanisms versus negating fate-suppressing mechanisms to engineer progenitor cells with multilineage differentiation potential. Deletion of the murine Gata2-77 enhancer, with a human equivalent that causes leukemia, downregulates the transcription factor GATA2 and blocks progenitor differentiation into erythrocytes, megakaryocytes, basophils, and granulocytes, but not macrophages. Using multiomics and single-cell analyses, we demonstrated that the enhancer orchestrates a balance between pro- and anti-fate circuitry in single cells. By increasing GATA2 expression, the enhancer instigates a fate-promoting mechanism while abrogating an innate immunity-linked, fate-suppressing mechanism. During embryogenesis, the suppressing mechanism dominated in enhancer mutant progenitors, thus yielding progenitors with a predominant monocytic differentiation potential. Coordinating fate-promoting and -suppressing circuits therefore averts deconstruction of a multifate system into a monopotent system and maintains critical progenitor heterogeneity and functionality. |
