Abstract
Myocyte enhancer factor 2B (MEF2B) is a transcription factor with mutation hotspots at K4, Y69 and D83 in diffuse large B-cell lymphoma (DLBCL). To provide insight into the regulatory network of MEF2B, in this study, we analyse global gene expression and DNA-binding patterns. We find that candidate MEF2B direct target genes include RHOB, RHOD, CDH13, ITGA5 and CAV1, and that indirect target genes of MEF2B include MYC, TGFB1, CARD11, MEF2C, NDRG1 and FN1. MEF2B overexpression increases HEK293A cell migration and epithelial–mesenchymal transition, and decreases DLBCL cell chemotaxis. K4E, Y69H and D83V MEF2B mutations decrease the capacity of MEF2B to activate transcription and decrease its' effects on cell migration. The K4E and D83V mutations decrease MEF2B DNA binding. In conclusion, our map of the MEF2B regulome connects MEF2B to drivers of oncogenesis.
Highlights
Myocyte enhancer factor 2B (MEF2B) is a transcription factor with mutation hotspots at K4, Y69 and D83 in diffuse large B-cell lymphoma (DLBCL)
MEF2B is amplified in 9% of ovarian carcinomas (28 out of 311 cases, TCGA provisional data11,12), 5% of uterine carcinomas (11 out of 240 cases13), 5% of adrenocortical carcinomas (4 out of 88 cases, TCGA provisional data11,12) and 3% of oesophageal carcinomas (6 out of 184 cases, TCGA provisional data11,12), indicating that MEF2B may act as an oncogene in these carcinomas
The 3,944 differentially expressed genes (DEGs) that were found between wild type (WT) MEF2B-V5 and untransfected cells (Benajmini–Hochberg (B–H) adjusted eBayes P values o0.05, Supplementary Data 1) are potential MEF2B target genes[19]
Summary
Myocyte enhancer factor 2B (MEF2B) is a transcription factor with mutation hotspots at K4, Y69 and D83 in diffuse large B-cell lymphoma (DLBCL). K4E, Y69H and D83V MEF2B mutations decrease the capacity of MEF2B to activate transcription and decrease its’ effects on cell migration. The four human MEF2 proteins, MEF2A, MEF2B, MEF2C and MEF2D, consist of an N-terminal DNA-binding MADS domain, a central MEF2 domain, and a C-terminal transcriptional activation domain[1]. We identify direct and indirect candidate target genes of MEF2B and associate these with changes in cell proliferation, survival, migration and epithelial–mesenchymal transition (EMT). We describe effects of MEF2B mutation on both DLBCL cell chemotaxis and the expression of lymphoma driver genes. Our data indicate that MEF2B mutations decrease target gene activation and alter cell migration
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