A novel role for <i>Lyl1</i> in primitive erythropoiesis

Abstract

Stem cell leukemia (<i>Scl</i> or <i>Tal1</i>) and lymphoblastic leukemia 1 (<i>Lyl1</i>) encode highly related members of the basic helix-loop-helix family of transcription factors that are co-expressed in the erythroid lineage. Previous studies have suggested that <i>Scl</i> is essential for primitive erythropoiesis. However, analysis of single-cell RNA-seq data of early embryos showed that primitive erythroid cells express both <i>Scl</i> and <i>Lyl1</i> Therefore, to determine whether <i>Lyl1</i> can function in primitive erythropoiesis, we crossed conditional <i>Scl</i> knockout mice with mice expressing a Cre recombinase under the control of the Epo receptor, active in erythroid progenitors. Embryos with 20% expression of <i>Scl</i> from E9.5 survived to adulthood. However, mice with reduced expression of <i>Scl</i> and absence of <i>Lyl1</i> (double knockout; DKO) died at E10.5 because of progressive loss of erythropoiesis. Gene expression profiling of DKO yolk sacs revealed loss of <i>Gata1</i> and many of the known target genes of the SCL-GATA1 complex. ChIP-seq analyses in a human erythroleukemia cell line showed that LYL1 exclusively bound a small subset of SCL targets including <i>GATA1.</i> Together, these data show for the first time that <i>Lyl1</i> can maintain primitive erythropoiesis.