DOT1L Methyltransferase Regulates Calcium Influx in Erythroid Progenitor Cells in Response to Erythropoietin
Erythropoietin (EPO) signaling plays a vital role in erythropoiesis by regulating proliferation and lineage-specific differentiation of murine hematopoietic progenitor cells (HPCs). An important downstream response of EPO signaling is calcium (Ca<sup>2+</sup>) influx, which is regulated...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-05-01
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| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/23/9/5137 |
| Summary: | Erythropoietin (EPO) signaling plays a vital role in erythropoiesis by regulating proliferation and lineage-specific differentiation of murine hematopoietic progenitor cells (HPCs). An important downstream response of EPO signaling is calcium (Ca<sup>2+</sup>) influx, which is regulated by transient receptor potential channel (TRPC) proteins, particularly TRPC2 and TRPC6. While EPO induces Ca<sup>2+</sup> influx through TRPC2, TRPC6 inhibits the function of TRPC2. Thus, interactions between TRPC2 and TRPC6 regulate the rate of Ca<sup>2+</sup> influx in EPO-induced erythropoiesis. In this study, we observed that the expression of TRPC6 in KIT-positive erythroid progenitor cells was regulated by DOT1L. DOT1L is a methyltransferase that plays an important role in many biological processes during embryonic development including early erythropoiesis. We previously reported that <i>Dot1l</i> knockout (<i>Dot1l<sup>KO</sup></i>) HPCs in the yolk sac failed to develop properly, which resulted in lethal anemia. In this study, we detected a marked downregulation of <i>Trpc6</i> gene expression in <i>Dot1l</i><i><sup>KO</sup></i> progenitor cells in the yolk sac compared to the wild type (WT). The promoter and the proximal regions of the <i>Trpc6</i> gene locus exhibited an enrichment of H3K79 methylation, which is mediated solely by DOT1L. However, the expression of <i>Trpc2</i>, the positive regulator of Ca<sup>2+</sup> influx, remained unchanged, resulting in an increased TRPC2/TRPC6 ratio. As the loss of DOT1L decreased TRPC6, which inhibited Ca<sup>2+</sup> influx by TRPC2, <i>Dot1l<sup>KO</sup></i> HPCs in the yolk sac exhibited accelerated and sustained elevated levels of Ca<sup>2+</sup> influx. Such heightened Ca<sup>2+</sup> levels might have detrimental effects on the growth and proliferation of HPCs in response to EPO. |
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| ISSN: | 1661-6596 1422-0067 |