Context-dependent regulation of hematopoietic lineage choice by HEBAlt.
Hematopoietic development is controlled by combinatorial interactions between E-protein transcription factors and other lineage regulators that operate in the context of gene-regulatory networks. The E-proteins HEB and E2A are critical for T cell and B cell development, but the mechanisms by which their activities are directed to different genes in each lineage are unclear. We found that a short form of HEB, HEBAlt, acts downstream of Delta-like (DL)-Notch signaling to promote T cell development. In this paper, we show that forced expression of HEBAlt in mouse hematopoietic progenitors inhibited B cell development, but it allowed them to adopt a myeloid fate. HEBAlt interfered with the activity of E2A homodimers and with the expression of the transcription factor Pax5, both of which are critical for B cell development. However, when combined with DL-Notch signaling, HEBAlt enhanced the generation of T cell progenitors at the expense of myeloid cells. The longer form of HEB, HEBCan, also inhibited E47 activity and Pax5 expression, but it did not collaborate with DL-Notch signaling to suppress myeloid potential. Therefore, HEBAlt can suppress B cell or myeloid potential in a context-specific manner, which suggests a role for this factor in maintaining T lineage priming prior to commitment.
Wang
Duncheng
D
Division of Molecular and Cellular Biology, Sunnybrook Research Institute, Toronto, Ontario, Canada.
Claus
Carol L
CL
Rajkumar
Paula
P
Braunstein
Marsela
M
Moore
Amanda J
AJ
Sigvardsson
Mikael
M
Anderson
Michele K
MK
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D019070:Cell Lineage / Q000235:genetics* / Q000276:immunology; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000276:immunology*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D038041:Lymphopoiesis / Q000235:genetics* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D051757:PAX5 Transcription Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology* / Q000378:metabolism; D051820:TCF Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D058125:Transcription Factor 7-Like 1 Protein
D051792:Basic Helix-Loop-Helix Proteins; D051757:PAX5 Transcription Factor; D020033:Protein Isoforms; D051820:TCF Transcription Factors; D058125:Transcription Factor 7-Like 1 Protein; C497282:Pax5 protein, mouse; C489532:Tcf12 protein, mouse; C544913:Tcf7l1 protein, mouse