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An erythroid-to-myeloid cell fate conversion is elicited by LSD1 inactivation

Lei Yu1, Greggory Myers1,2, Chia-Jui Ku1

  • 1Department of Cell and Developmental Biology.

Blood
|July 29, 2021
PubMed

Insights

Histone demethylase LSD1 normally promotes red blood cell development. Inactivating LSD1 causes stem cells to become myeloid cells instead of red blood cells, a switch reversible by blocking myeloid factors.

Area of Science:

  • Hematopoiesis
  • Epigenetics
  • Gene Regulation

Background:

  • Histone H3 lysine 4 methylation (H3K4Me) typically activates genes.
  • Histone demethylase KDM1a/LSD1 removes H3K4 methyl groups and is a therapeutic target for diseases like sickle cell disease.
  • LSD1 inhibition can induce fetal globin genes, relevant for β-globinopathies.

Purpose of the Study:

  • To investigate the effects of LSD1 inhibition on definitive erythropoiesis (red blood cell development) in adult mice.
  • To understand the role of LSD1 in maintaining erythroid lineage commitment.

Main Methods:

  • Conditional inactivation of the Lsd1 gene in adult red blood cells using a Gata1creERT2 BAC transgene in mice.
  • Analysis of hematopoietic stem and progenitor cells (HSPCs) from mice and humans.
  • Examination of transcription factor activity (PU.1, CEBPα, RUNX1).

Main Results:

  • Erythroid-specific loss of LSD1 in mice blocked erythroid progenitor differentiation.
  • LSD1 inactivation led to the expansion of myeloid progenitor-like cells, shifting differentiation from erythroid to myeloid.
  • A similar myeloid lineage conversion was observed in human HSPCs, associated with increased myeloid transcription factors.
  • Simultaneous inhibition of PU.1 or RUNX1 with LSD1 inhibition rescued the erythroid phenotype.

Conclusions:

  • LSD1 promotes erythropoiesis by actively repressing myeloid cell fate in adult erythroid progenitors.
  • Inhibiting the myeloid differentiation pathway can reverse the lineage switch caused by LSD1 inactivation.
  • These findings highlight LSD1's crucial role in directing hematopoietic stem cell differentiation towards the erythroid lineage.

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