Open Access

An intricate regulatory circuit between FLI1 and GATA1/GATA2/LDB1/ERG dictates erythroid vs. megakaryocytic differentiation

  • Authors:
    • Chunlin Wang
    • Maoting Hu
    • Kunlin Yu
    • Wuling Liu
    • Anling Hu
    • Yi Kuang
    • Lei Huang
    • Babu Gajendran
    • Eldad Zacksenhaus
    • Xiao Xiao
    • Yaacov Ben‑David
  • View Affiliations

  • Published online on: April 26, 2024     https://doi.org/10.3892/mmr.2024.13231
  • Article Number: 107
  • Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

During hematopoiesis, megakaryocytic erythroid progenitors (MEPs) differentiate into megakaryocytic or erythroid lineages in response to specific transcriptional factors, yet the regulatory mechanism remains to be elucidated. Using the MEP‑like cell line HEL western blotting, RT‑qPCR, lentivirus‑mediated downregulation, flow cytometry as well as chromatin immunoprecipitation (ChIp) assay demonstrated that the E26 transformation‑specific (ETS) transcription factor friend leukemia integration factor 1 (Fli‑1) inhibits erythroid differentiation. The present study using these methods showed that while FLI1‑mediated downregulation of GATA binding protein 1 (GATA1) suppresses erythropoiesis, its direct transcriptional induction of GATA2 promotes megakaryocytic differentiation. GATA1 is also involved in megakaryocytic differentiation through regulation of GATA2. By contrast to FLI1, the ETS member erythroblast transformation‑specific‑related gene (ERG) negatively controls GATA2 and its overexpression through exogenous transfection blocks megakaryocytic differentiation. In addition, FLI1 regulates expression of LIM Domain Binding 1 (LDB1) during erythroid and megakaryocytic commitment, whereas shRNA‑mediated depletion of LDB1 downregulates FLI1 and GATA2 but increases GATA1 expression. In agreement, LDB1 ablation using shRNA lentivirus expression blocks megakaryocytic differentiation and modestly suppresses erythroid maturation. These results suggested that a certain threshold level of LDB1 expression enables FLI1 to block erythroid differentiation. Overall, FLI1 controlled the commitment of MEP to either erythroid or megakaryocytic lineage through an intricate regulation of GATA1/GATA2, LDB1 and ERG, exposing multiple targets for cell fate commitment and therapeutic intervention.
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June-2024
Volume 29 Issue 6

Print ISSN: 1791-2997
Online ISSN:1791-3004

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Spandidos Publications style
Wang C, Hu M, Yu K, Liu W, Hu A, Kuang Y, Huang L, Gajendran B, Zacksenhaus E, Xiao X, Xiao X, et al: An intricate regulatory circuit between FLI1 and GATA1/GATA2/LDB1/ERG dictates erythroid vs. megakaryocytic differentiation. Mol Med Rep 29: 107, 2024
APA
Wang, C., Hu, M., Yu, K., Liu, W., Hu, A., Kuang, Y. ... Ben‑David, Y. (2024). An intricate regulatory circuit between FLI1 and GATA1/GATA2/LDB1/ERG dictates erythroid vs. megakaryocytic differentiation. Molecular Medicine Reports, 29, 107. https://doi.org/10.3892/mmr.2024.13231
MLA
Wang, C., Hu, M., Yu, K., Liu, W., Hu, A., Kuang, Y., Huang, L., Gajendran, B., Zacksenhaus, E., Xiao, X., Ben‑David, Y."An intricate regulatory circuit between FLI1 and GATA1/GATA2/LDB1/ERG dictates erythroid vs. megakaryocytic differentiation". Molecular Medicine Reports 29.6 (2024): 107.
Chicago
Wang, C., Hu, M., Yu, K., Liu, W., Hu, A., Kuang, Y., Huang, L., Gajendran, B., Zacksenhaus, E., Xiao, X., Ben‑David, Y."An intricate regulatory circuit between FLI1 and GATA1/GATA2/LDB1/ERG dictates erythroid vs. megakaryocytic differentiation". Molecular Medicine Reports 29, no. 6 (2024): 107. https://doi.org/10.3892/mmr.2024.13231