Sumoylation of CCAAT/enhancer-binding protein α promotes the biased primitive hematopoiesis of zebrafish

Hematopoiesis is evolutionarily conserved from zebrafish to mammals, and this includes both primitive and definitive waves during embryogenesis. Primitive hematopoiesis is dominated by erythropoiesis with limited myelopoiesis. Protein sumoylation, a ubiquitination-like posttranslational protein modification, is implicated in a variety of biochemical processes, most notably in transcriptional repression. We show here that the loss of 6 small ubiquitin-related modifier (SUMO) paralogs triggers a sharp up-regulation of the myeloid-specific marker mpo and down-regulation of the erythroid-specific marker gata1 in myelo-erythroid progenitor cells (MPCs) in the intermediate cell mass (ICM) during primitive hematopoiesis. Accordingly, in transgenic zebrafish lines, hyposumoylation expands myelopoiesis at the expense of erythropoiesis. ASUMO-CCAAT/enhancer-binding protein alpha (SUMO-C/ebp alpha) fusion restores the normal myelopoiesis/erythropoiesis balance, suggesting that sumoylation status of C/ebp alpha contributes to myelo-erythroid lineage determination. Our results therefore implicate sumoylation in early lineage determination and reveal the possible molecular mechanism underlying the puzzling biased primitive hematopoiesis in vertebrates. (Blood. 2011;117(26):7014-7020)