Unknown

Dataset Information

0

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


ABSTRACT: 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.

SUBMITTER: Johnson KD 

PROVIDER: S-EPMC7596813 | biostudies-literature |

REPOSITORIES: biostudies-literature

Similar Datasets

| S-EPMC4939618 | biostudies-literature
| S-EPMC7021008 | biostudies-literature
| S-EPMC5484588 | biostudies-literature
2020-06-03 | GSE134439 | GEO
| S-EPMC7882614 | biostudies-literature
| S-EPMC4641806 | biostudies-literature
| S-EPMC5748852 | biostudies-literature
| S-EPMC3737729 | biostudies-literature
| PRJNA555423 | ENA
| S-EPMC4913252 | biostudies-literature