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...
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MDPI AG
2022-05-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/9/5137 |
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| author | Yi Feng Shaon Borosha Anamika Ratri Eun Bee Lee Huizhen Wang Timothy A. Fields William H. Kinsey Jay L. Vivian M. A. Karim Rumi Patrick E. Fields |
| author_facet | Yi Feng Shaon Borosha Anamika Ratri Eun Bee Lee Huizhen Wang Timothy A. Fields William H. Kinsey Jay L. Vivian M. A. Karim Rumi Patrick E. Fields |
| author_sort | Yi Feng |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T04:02:59Z |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T04:02:59Z |
| publishDate | 2022-05-01 |
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| spelling | doaj.art-0f4f3a6af3044f59aaa1f9dae9fa31ed2023-11-23T08:27:38ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-05-01239513710.3390/ijms23095137DOT1L Methyltransferase Regulates Calcium Influx in Erythroid Progenitor Cells in Response to ErythropoietinYi Feng0Shaon Borosha1Anamika Ratri2Eun Bee Lee3Huizhen Wang4Timothy A. Fields5William H. Kinsey6Jay L. Vivian7M. A. Karim Rumi8Patrick E. Fields9Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USADepartment of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USADepartment of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USADepartment of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USADepartment of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS 66160, USADepartment of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USADepartment of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS 66160, USADepartment of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USADepartment of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USADepartment of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USAErythropoietin (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.https://www.mdpi.com/1422-0067/23/9/5137DOT1Lerythroid progenitorserythropoietinTRPC6calcium influx |
| spellingShingle | Yi Feng Shaon Borosha Anamika Ratri Eun Bee Lee Huizhen Wang Timothy A. Fields William H. Kinsey Jay L. Vivian M. A. Karim Rumi Patrick E. Fields DOT1L Methyltransferase Regulates Calcium Influx in Erythroid Progenitor Cells in Response to Erythropoietin International Journal of Molecular Sciences DOT1L erythroid progenitors erythropoietin TRPC6 calcium influx |
| title | DOT1L Methyltransferase Regulates Calcium Influx in Erythroid Progenitor Cells in Response to Erythropoietin |
| title_full | DOT1L Methyltransferase Regulates Calcium Influx in Erythroid Progenitor Cells in Response to Erythropoietin |
| title_fullStr | DOT1L Methyltransferase Regulates Calcium Influx in Erythroid Progenitor Cells in Response to Erythropoietin |
| title_full_unstemmed | DOT1L Methyltransferase Regulates Calcium Influx in Erythroid Progenitor Cells in Response to Erythropoietin |
| title_short | DOT1L Methyltransferase Regulates Calcium Influx in Erythroid Progenitor Cells in Response to Erythropoietin |
| title_sort | dot1l methyltransferase regulates calcium influx in erythroid progenitor cells in response to erythropoietin |
| topic | DOT1L erythroid progenitors erythropoietin TRPC6 calcium influx |
| url | https://www.mdpi.com/1422-0067/23/9/5137 |
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