The transcription factors E2A and HEB act in concert to induce the expression of FOXO1 in the common lymphoid progenitor

Proc Natl Acad Sci U S A. 2011 Oct 18;108(42):17402-7. doi: 10.1073/pnas.1111766108. Epub 2011 Oct 4.

Abstract

Recent studies have identified a number of transcriptional regulators, including E proteins, EBF1, FOXO1, and PAX5, that act together to orchestrate the B-cell fate. However, it still remains unclear as to how they are linked at the earliest stages of B-cell development. Here, we show that lymphocyte development in HEB-ablated mice exhibits a partial developmental arrest, whereas B-cell development in E2A(+/-)HEB(-/-) mice is completely blocked at the LY6D(-) common lymphoid progenitor stage. We show that the transcription signatures of E2A- and HEB-ablated common lymphoid progenitors significantly overlap. Notably, we found that Foxo1 expression was substantially reduced in the LY6D(-) HEB- and E2A-deficient cells. Finally, we show that E2A binds to enhancer elements across the FOXO1 locus to activate Foxo1 expression, linking E2A and FOXO1 directly in a common pathway. In summary, the data indicate that the earliest event in B-cell specification involves the induction of FOXO1 expression and requires the combined activities of E2A and HEB.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antigens, Ly / immunology
  • B-Lymphocytes / cytology
  • B-Lymphocytes / immunology
  • B-Lymphocytes / metabolism
  • Basic Helix-Loop-Helix Transcription Factors / deficiency
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / immunology*
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors / genetics*
  • GPI-Linked Proteins / immunology
  • Gene Expression Regulation, Developmental
  • Hematopoiesis / genetics
  • Hematopoiesis / immunology
  • Inhibitor of Differentiation Protein 2 / genetics
  • Inhibitor of Differentiation Protein 2 / immunology
  • Inhibitor of Differentiation Proteins / genetics
  • Inhibitor of Differentiation Proteins / immunology
  • Lymphoid Progenitor Cells / cytology
  • Lymphoid Progenitor Cells / immunology*
  • Lymphoid Progenitor Cells / metabolism
  • Mice
  • Mice, Knockout

Substances

  • Antigens, Ly
  • Basic Helix-Loop-Helix Transcription Factors
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors
  • Foxo1 protein, mouse
  • GPI-Linked Proteins
  • Idb2 protein, mouse
  • Inhibitor of Differentiation Protein 2
  • Inhibitor of Differentiation Proteins
  • Ly6d protein, mouse
  • Tcf12 protein, mouse
  • Tcf3 protein, mouse
  • Idb3 protein, mouse

Associated data

  • GEO/GSE27402