Regulation of lymphoid versus myeloid fate 'choice' by the transcription factor Mef2c

Abstract

Despite advances in the identification of lymphoid-restricted progenitor cells, the transcription factors essential for their generation remain to be identified. Here we describe an unexpected function for the myeloid oncogene product Mef2c in lymphoid development. Mef2c deficiency was associated with profound defects in the production of B cells, T cells, natural killer cells and common lymphoid progenitor cells and an enhanced myeloid output. In multipotent progenitors, Mef2c was required for the proper expression of several key lymphoid regulators and restriction of the myeloid fate. Our studies also show that Mef2c was a critical transcriptional target of the transcription factor PU.1 during lymphopoiesis. Thus, Mef2c is a crucial component of the transcriptional network that regulates cell fate 'choice' in multipotent progenitors.

Regulation of Follicular B Cell Differentiation by the Related E26 Transformation-Specific Transcription Factors PU.1, Spi-B, and Spi-C

“…Myocyteenhancer factor 2c (Mef2c) is a MADS-box transcription factor that is important for B cell differentiation and function (39,40). We recently showed that Mef2c is directly activated by PU.1 in B cells (39). As would be predicted by this observation, Mef2c (Fig.…”

“…6A, Cd19 transcripts (encoding the CD19 cell surface marker) were expressed in both FO-I and FO-II/MZ-P B cell subsets. Myocyteenhancer factor 2c (Mef2c) is a MADS-box transcription factor that is important for B cell differentiation and function (39,40). We recently showed that Mef2c is directly activated by PU.1 in B cells (39).…”

“…Chromatin was prepared from WEHI-279 cells expressing 3XFLAG-tagged Spi-C as well as from uninfected control cells and immunoprecipitated with either anti-FLAG or control Abs. qPCR was used to determine the relative amount of immunoprecipitated DNA from regulatory regions including the IgH intronic enhancer (Em), which has previously been shown to interact with Spi-C (29), a region of the Mef2c intronic enhancer previously shown to interact with PU.1 (Mef2c C+D) (39), and the Fcer2a promoter region (Fcer2a-p). Negative controls included the proximal promoter regions of the erythrocyte-specific gene erythropoietin receptor (EpoR-p), the promoter of the T cell-specific CD3g gene (CD3g-p), and the ubiquitously expressed Hprt and Gapdh genes.…”

Logical modeling of lymphoid and myeloid cell specification and transdifferentiation

“…1A) (13,14). The B-cell lineage is further controlled by Mef2c, the interleukine 7 receptor (IL7r), Ets1, Foxo1, Ebf1, and Pax5 (15,16,17). The specification of the myeloid GMPs depends on C/EBPα (6), which is regulated by Runx1 (runt-related transcription factor 1) (18).…”

MAP Kinase Cascades in Antigen Receptor Signaling and Physiology

“…shown by the conditional deletion of Mef2c in mice (Stehling-Sun, Dade, Nutt, DeKoter, & Camargo, 2009). The critical role of Mef2c for proliferation and survival of mature B cells after BCR stimulation, but not after LPS or CD40 stimulation, through the induction of the cell cycle promoting gene Cyclin D2 and the prosurvival gene Bcl-xL suggests a role of Mef2c in pre-BCR-dependent cell proliferation and survival (Wilker et al, 2008).…”