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

J Exp Med. 2020 Nov 2;217(11):e20191526. doi: 10.1084/jem.20191526.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Animals
  • Basophils / physiology
  • Cell Differentiation / genetics*
  • Cells, Cultured
  • Enhancer Elements, Genetic / genetics
  • Erythrocytes / physiology
  • Female
  • GATA2 Transcription Factor / genetics*
  • Gene Deletion*
  • Germ-Line Mutation*
  • Hematopoiesis / genetics
  • Humans
  • Macrophages / physiology
  • Megakaryocytes / physiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Single-Cell Analysis
  • Stem Cells / physiology*

Substances

  • GATA2 Transcription Factor
  • GATA2 protein, human
  • Gata2 protein, mouse