Threshold Levels of Gfi1 Maintain E2A Activity for B Cell Commitment via Repression of Id1

PLoS One. 2016 Jul 28;11(7):e0160344. doi: 10.1371/journal.pone.0160344. eCollection 2016.

Abstract

A regulatory circuit that controls myeloid versus B lymphoid cell fate in hematopoietic progenitors has been proposed, in which a network of the transcription factors Egr1/2, Nab, Gfi1 and PU.1 forms the core element. Here we show that a direct link between Gfi1, the transcription factor E2A and its inhibitor Id1 is a critical element of this regulatory circuit. Our data suggest that a certain threshold of Gfi1 is required to gauge E2A activity by adjusting levels of Id1 in multipotent progenitors, which are the first bipotential myeloid/lymphoid-restricted progeny of hematopoietic stem cells. If Gfi1 levels are high, Id1 is repressed enabling E2A to activate a specific set of B lineage genes by binding to regulatory elements for example the IL7 receptor gene. If Gfi1 levels fall below a threshold, Id1 expression increases and renders E2A unable to function, which prevents hematopoietic progenitors from engaging along the B lymphoid lineage.

MeSH terms

  • Animals
  • B-Lymphocytes / cytology*
  • B-Lymphocytes / metabolism
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Cell Differentiation
  • Cell Lineage
  • Cells, Cultured
  • DNA-Binding Proteins / metabolism*
  • Gene Expression Profiling
  • Inhibitor of Differentiation Protein 1 / metabolism*
  • Mice
  • Mice, Transgenic
  • Transcription Factors / metabolism*

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • DNA-Binding Proteins
  • Gfi1 protein, mouse
  • Idb1 protein, mouse
  • Inhibitor of Differentiation Protein 1
  • Tcf3 protein, mouse
  • Transcription Factors

Grant support

JF was supported by a fellowship from the Fonds recherche Québec-Santé. CV was supported by a fellowship from the Canadian Institute for Health Research (CIHR). CK is supported by funds of the Deutsche Krebshilfe and the Jakstädt-foundation. TM holds a Canada Research Chair (Tier 1). This work was supported by CIHR grants to TM (MOP – 111011) and FR/TM (MOP-106427).