Mef2C is a lineage-restricted target of Scl/Tall and regulates megakaryopoiesis and B-cell homeostasis

The basic helix-loop-helix transcription factor stem cell leukemia gene (Scl)isa master regulator for hematopoiesis essential for hematopoietic specification and proper differentiation of the erythroid and megakaryocyte lineages. However, the critical downstream targets of Scl remain undefined. Here, we identified a novel Scl target gene, transcription factor myocyte enhancer factor2C(Mef2C) from Scl^fl/^fI fetal liver progenitor cell lines. Analysis of Mef2C-embryos showed that Mef2C, in contrast to Scl, is not essential for specification into primitive or definitive hematopoietic lineages. However, adult VavCre+Mef2C^tlFI mice exhibited platelet defects similar to those observed in Scl- deficient mice. The platelet counts were reduced, whereas platelet size was increased and the platelet shape and granularity were altered. Furthermore, megakaryopoi- esis was severely impaired in vitro. Chromatin immunoprecipitation microarray hy-bridization analysis revealed that Mef2C is directly regulated by Scl in megakaryo- cytic cells, but not in erythroid cells. In addition, an Scl-independent requirement for Mef2C in B-lymphoid homeostasis was observed in Mef2C-deficient mice, characterized as severe age-dependent reduction of specific B-cell progenitor populations reminiscent of premature aging. In summary, this work identifies Mef2C as an integral member of hematopoietic transcription factors with distinct upstream regulatory mechanisms and functional requirements in megakaryocyte and B-lymphoid lineages.