E2A proteins promote development of lymphoid-primed multipotent progenitors.
The first lymphoid-restricted progeny of hematopoietic stem cells (HSCs) are lymphoid-primed multipotent progenitors (LMPPs), which have little erythromyeloid potential but retain lymphoid, granulocyte, and macrophage differentiation capacity. Despite recent advances in the identification of LMPPs, the transcription factors essential for their generation remain to be identified. Here, we demonstrated that the E2A transcription factors were required for proper development of LMPPs. Within HSCs and LMPPs, E2A proteins primed expression of a subset of lymphoid-associated genes and prevented expression of genes that are not normally prevalent in these cells, including HSC-associated and nonlymphoid genes. E2A proteins also restricted proliferation of HSCs, MPPs, and LMPPs and antagonized differentiation of LMPPs toward the myeloid fate. Our results reveal that E2A proteins play a critical role in supporting lymphoid specification from HSCs and that the reduced generation of LMPPs underlies the severe lymphocyte deficiencies observed in E2A-deficient mice.
Dias
Sheila
S
Department of Pathology, The University of Chicago, Chicago, IL 60637, USA.
Månsson
Robert
R
Gurbuxani
Sandeep
S
Sigvardsson
Mikael
M
Kee
Barbara L
BL
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000172:deficiency / Q000276:immunology / Q000378:metabolism*; D002454:Cell Differentiation; D019070:Cell Lineage; D049109:Cell Proliferation; D015870:Gene Expression; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D008214:Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D054503:Lymphoid Progenitor Cells / Q000166:cytology* / Q000378:metabolism*; D038041:Lymphopoiesis; D051379:Mice; D018345:Mice, Knockout; D039902:Multipotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D023461:Myeloid Progenitor Cells / Q000166:cytology / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
D051792:Basic Helix-Loop-Helix Proteins; D014157:Transcription Factors; C075668:Tcf3 protein, mouse