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The mechanisms underlying the silencing of alternative fate potentials in very early B cell precursors remain unclear. Using gain- and loss-of-function approaches together with a synthetic Zinc-finger polypeptide (6ZFP) engineered to prevent transcription factor binding to a defined cis element, we show that the transcription factor EBF1 promotes B cell lineage commitment by directly repressing expression of the T-cell-lineage-requisite Gata3 gene. Ebf1-deficient lymphoid progenitors exhibited increased T cell lineage potential and elevated Gata3 transcript expression, whereas enforced EBF1 expression inhibited T cell differentiation and caused rapid loss of Gata3 mRNA. Notably, 6ZFP-mediated perturbation of EBF1 binding to a Gata3 regulatory region restored Gata3 expression, abrogated EBF1-driven suppression of T cell differentiation, and prevented B cell differentiation via a GATA3-dependent mechanism. Furthermore, EBF1 binding to Gata3 regulatory sites induced repressive histone modifications across this region. These data identify a transcriptional circuit critical for B cell lineage commitment.

Original publication

DOI

10.1016/j.immuni.2013.01.014

Type

Journal article

Journal

Immunity

Publication Date

23/05/2013

Volume

38

Pages

930 - 942

Keywords

Animals, B-Lymphocytes, Cell Differentiation, Cell Lineage, Cells, Cultured, Female, GATA3 Transcription Factor, Gene Expression, Gene Expression Regulation, Hepatocyte Nuclear Factor 1-alpha, Histones, Lymphoid Progenitor Cells, Lymphopoiesis, Mice, Mice, Inbred C57BL, RNA, Messenger, Receptor, Notch1, T-Lymphocytes, Trans-Activators, Transcription, Genetic, Zinc Fingers