Constructing and deconstructing GATA2-regulated cell fate programs to establish developmental trajectories

Kirby D. Johnson, Daniel J. Conn, Evgenia Shishkova, Koichi R. Katsumura, Peng Liu, Siqi Shen, Erik A. Ranheim, Sean G. Kraus, Weixin Wang, Katherine R. Calvo, Amy P. Hsu, Steven M. Holland (+3 others)
2020 Journal of Experimental Medicine  
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
more » ... ownregulates 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.
doi:10.1084/jem.20191526 pmid:32736380 fatcat:7syjtjl2ijbmdjhmwvt77sefdy