The paralogous hematopoietic regulators Lyl1and Sclare coregulated by Ets and GATA factors, but Lyl1cannot rescue the early Scl–/–phenotype

Transcription factors are key regulators of hematopoietic stem cells (HSCs), yet the molecular mechanisms that control their expression are largely unknown. Previously, we demonstrated that expression of Scl/Tal1, a transcription factor required for the specification of HSCs, is controlled by Ets and GATA factors. Here we characterize the molecular mechanisms controlling expression of Lyl1, a paralog of Sclalso required for HSC function. Two closely spaced promoters directed expression to hematopoietic progenitor, megakaryocytic, and endothelial cells in transgenic mice. Conserved binding sites required for promoter activity were bound in vivo by GATA-2 and the Ets factors Fli1, Elf1, Erg, and PU.1. However, despite coregulation of Scland Lyl1by the same Ets and GATA factors, Sclexpression was initiated prior to Lyl1in embryonic stem (ES) cell differentiation assays. Moreover, ectopic expression of Sclbut not Lyl1rescued hematopoietic differentiation in Scl−/−ES cells, thus providing a molecular explanation for the vastly different phenotypes of Scl−/−and Lyl1−/−mouse embryos. Furthermore, coregulation of Scland Lyl1later during development may explain the mild phenotype of Scl−/−adult HSCs.