The c-Myb target gene neuromedin U functions as a novel cofactor during the early stages of erythropoiesis

Abstract

IntroductionErythropoiesis is the process by which hematopoietic cells mature into red blood cells. The early stages of erythropoiesis have been studied through colony-forming assays in which the cells first committed to erythropoiesis are burst-forming unit-erythroid (BFU-E) followed by colony-forming unit-erythroid (CFU-E). 1 The CFU-Es undergo a series of cell divisions to give rise to mature erythroblasts that become hemoglobinized. Reticulocytes form after the nuclei extrude from the hemoglobinized erythroblasts. Finally, the reticulocytes give rise to red blood cells. Extrinsic signals mediated by cytokines and other factors in the microenvironment have been reported to be critical during red blood cell development. For instance, the interaction of stem cell factor (SCF) with c-Kit receptor, 2 which is expressed in immature hematopoietic cells until the CFU-E stage, 3 and the interaction of erythropoietin (EPO) with the EPO receptor (EPOR), 4 which is expressed on erythroid progenitors until later erythroblast stages, 5 are critical for erythroid progenitor cell survival, expansion, and differentiation.Mouse models, in which transcription factor genes have targeted mutations, revealed that regulation of erythroid development is important at the transcription level. [6][7][8][9][10][11][12] For example, the c-myb proto-oncogene encodes the c-Myb transcription factor that is expressed predominantly in immature hematopoietic cells, and as these cells mature, c-Myb expression declines. c-Myb has been reported to play an important role in cell survival, proliferation, and differentiation. 13 Mice that are homozygous for the c-myb null allele die of severe anemia at embryonic day 15 (E15) because of diminished erythropoiesis in the fetal liver. 12 In K562 cells engineered to express a tamoxifen-inducible dominant negative Myb (MERT), we identified the neuropeptide neuromedin U (NmU) as a novel candidate Myb target gene but did not demonstrate that Myb directly regulates NmU expression. 14 An examination of NmU mRNA expression in nondiseased tissue revealed that it is expressed the highest in brain, gut, and bone marrow. 15 Studies of NmU function in rat brain tissue have revealed that it decreases appetite and body weight [16][17][18][19][20] and increases gross locomotor activity, body temperature, heat production, oxygen consumption, and bone mass. 16,18,21 In the gut, NmU has been reported to regulate local blood flow and ion transport. [22][23][24] Although NmU has been reported to stimulate cytokine production in the murine Th2-type T-cell clone D10.G4.1 25 and promote mast cell-mediated inflammation, 26 the physiologic function of NmU during hematopoiesis in the bone marrow remains ill defined. Given that c-Myb is required during erythropoiesis and that NmU is a candidate Myb target gene, we postulated that c-Myb induces NmU expression in normal hematopoietic cells to facilitate erythropoiesis.In this study, we demonstrate that NmU is a novel extrinsic factor that is important for the production of BFU-E a...

A Genome-wide Framework for Mapping Gene Regulation via Cellular Genetic Screens

“…Targeting of multiple candidate enhancers decreased expression of the same gene, NMU , which encodes neuromedin U, a neuropeptide that plays roles in inflammation as well as erythropoiesis (Gambone et al, 2011). One candidate enhancer was associated with light repression of NMU (Figure 5D, i; located 30.5 kb upstream of the NMU TSS).…”

Functional Regulation of Pre-B-cell Leukemia Homeobox Interacting Protein 1 (PBXIP1/HPIP) in Erythroid Differentiation

“…It is well documented that erythropoietin regulates the expression of many genes that are involved in erythropoiesis. For instance, c-MYB and NUM genes are induced in response to Epo treatment at day 8 in CD34 ϩ cells (36). Indeed GATA1 itself is induced in response to Epo signaling (37).…”