The Molecular Signature of Megakaryocyte-Erythroid Progenitors Reveals a Role for the Cell Cycle in Fate Specification
Yi-Chien Lu,
Chad Sanada,
Juliana Xavier-Ferrucio,
Lin Wang,
Ping-Xia Zhang,
H. Leighton Grimes,
Meenakshi Venkatasubramanian,
Kashish Chetal,
Bruce Aronow,
Nathan Salomonis,
Diane S. Krause
Affiliations
Yi-Chien Lu
Department of Laboratory Medicine and Yale Stem Cell Center, Yale School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA; Corresponding author
Chad Sanada
Department of Laboratory Medicine and Yale Stem Cell Center, Yale School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA
Juliana Xavier-Ferrucio
Department of Laboratory Medicine and Yale Stem Cell Center, Yale School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA
Lin Wang
Department of Laboratory Medicine and Yale Stem Cell Center, Yale School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA
Ping-Xia Zhang
Department of Laboratory Medicine and Yale Stem Cell Center, Yale School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA
H. Leighton Grimes
Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA; Department of Pediatrics, University of Cincinnati School of Medicine, Cincinnati, OH 45229, USA
Meenakshi Venkatasubramanian
Division of Biomedical Informatics, Cincinnati Children’s Hospital, 3333 Burnet Avenue, Cincinnati, OH 45229, USA
Kashish Chetal
Division of Biomedical Informatics, Cincinnati Children’s Hospital, 3333 Burnet Avenue, Cincinnati, OH 45229, USA
Bruce Aronow
Department of Pediatrics, University of Cincinnati School of Medicine, Cincinnati, OH 45229, USA; Division of Biomedical Informatics, Cincinnati Children’s Hospital, 3333 Burnet Avenue, Cincinnati, OH 45229, USA
Nathan Salomonis
Department of Pediatrics, University of Cincinnati School of Medicine, Cincinnati, OH 45229, USA; Division of Biomedical Informatics, Cincinnati Children’s Hospital, 3333 Burnet Avenue, Cincinnati, OH 45229, USA
Diane S. Krause
Department of Laboratory Medicine and Yale Stem Cell Center, Yale School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA
Summary: Megakaryocytic-erythroid progenitors (MEPs) give rise to the cells that produce red blood cells and platelets. Although the mechanisms underlying megakaryocytic (MK) and erythroid (E) maturation have been described, those controlling their specification from MEPs are unknown. Single-cell RNA sequencing of primary human MEPs, common myeloid progenitors (CMPs), megakaryocyte progenitors, and E progenitors revealed a distinct transitional MEP signature. Inferred regulatory transcription factors (TFs) were associated with differential expression of cell cycle regulators. Genetic manipulation of selected TFs validated their role in lineage specification and demonstrated coincident modulation of the cell cycle. Genetic and pharmacologic modulation demonstrated that cell cycle activation is sufficient to promote E versus MK specification. These findings, obtained from healthy human cells, lay a foundation to study the mechanisms underlying benign and malignant disease states of the megakaryocytic and E lineages. : Bipotent megakaryocytic-erythroid progenitors (MEPs) produce megakaryocytic and erythroid cells. Using single-cell RNA sequencing of primary human MEPs and their upstream and downstream progenitors, Lu et al. show that MEPs are a unique transitional population. Functional and molecular studies show that MEP lineage fate is toggled by cell cycle speed.
