Transcriptional regulation of lysophosphatidic acid receptors 2 and 3 regulates myeloid commitment of hematopoietic stem cells
Journal
American Journal of Physiology - Cell Physiology
Journal Volume
320
Journal Issue
4
Pages
C509-C519
Date Issued
2021
Author(s)
Abstract
Lysophosphatidic acid (LPA) is one of the lipids identified to be involved in stem cell differentiation. It exerts various functions through activation of G protein-coupled lysophosphatidic acid receptors (LPARs). In previous studies, we have demonstrated that activation of LPA receptor 3 (LPA3) promotes erythropoiesis of human hematopoietic stem cells (HSCs) and zebrafish using molecular and pharmacological approaches. Our results show that treatment with lysophosphatidic acid receptor 2 (LPA2) agonist suppressed erythropoiesis, whereas activation of LPA3 by 1-oleoyl-2-methyl-sn-glycero-3-phosphothionate (2S-OMPT) promoted it, both in vitro and in vivo. Furthermore, we have demonstrated the inhibitory role of LPA3 during megakaryopoiesis. However, the mechanism underlying these observations remains elusive. In the present study, we suggest that the expression pattern of LPARs may be correlated with the transcriptional factors GATA-1 and GATA-2 at different stages of myeloid progenitors. We determined that manipulation of GATA factors affected the expression levels of LPA2 and LPA3 in K562 leukemia cells. Using luciferase assays, we demonstrate that the promoter regions of LPAR2 and LPAR3 genes were regulated by these GATA factors in HEK293T cells. Mutation of GATA-binding sites in these regions abrogated luciferase activity, suggesting that LPA2 and LPA3 are regulated by GATA factors. Moreover, physical interaction between GATA factors and the promoter region of LPAR genes was verified in K562 cells using chromatin immunoprecipitation (ChIP) studies. Taken together, our results suggest that balance between LPA2 and LPA3 expression, which may be determined by GATA factors, is a regulatory switch for lineage commitment in myeloid progenitors. The expression-level balance of LPA receptor subtypes represents a novel mechanism regulating erythropoiesis and megakaryopoiesis. Copyright ? 2021 the American Physiological Society
Subjects
GATA1 protein, human; GATA2 protein, human; LPAR2 protein, human; LPAR3 protein, human; lysophosphatidic acid receptor; transcription factor GATA 1; transcription factor GATA 2; binding site; cell lineage; erythropoiesis; genetic transcription; genetics; HEK293 cell line; hematopoiesis; hematopoietic stem cell; human; K-562 cell line; metabolism; promoter region; signal transduction; thrombocytopoiesis; Binding Sites; Cell Lineage; Erythropoiesis; GATA1 Transcription Factor; GATA2 Transcription Factor; HEK293 Cells; Hematopoiesis; Hematopoietic Stem Cells; Humans; K562 Cells; Promoter Regions, Genetic; Receptors, Lysophosphatidic Acid; Signal Transduction; Thrombopoiesis; Transcription, Genetic
Type
journal article