Blood Journal
Leading the way in experimental and clinical research in hematology

Corepressor Rcor1 is essential for murine erythropoiesis

  1. Huilan Yao1,
  2. Devorah C. Goldman2,3,
  3. Tamilla Nechiporuk1,
  4. Sunita Kawane4,
  5. Shannon K. McWeeney3,4,5,
  6. Jeffrey W. Tyner3,6,
  7. Guang Fan7,
  8. Marc A. Kerenyi8,
  9. Stuart H. Orkin8,9,
  10. William H. Fleming2,3, and
  11. Gail Mandel1,10
  1. 1Vollum Institute,
  2. 2Department of Pediatrics, Oregon Stem Cell Center,
  3. 3Knight Cancer Institute,
  4. 4Oregon Clinical and Translational Research Institute,
  5. 5Division of Bioinformatics and Computational Biology,
  6. 6Department of Cell and Developmental Biology,
  7. 7Department of Pathology, Oregon Health & Science University, Portland, OR;
  8. 8Division of Hematology/Oncology, Boston Children's Hospital and Dana-Farber Cancer Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA;
  9. 9Howard Hughes Medical Institute, Boston, MA; and
  10. 10Howard Hughes Medical Institute, Portland, OR

Key Points

  • Rcor1 knockout mice show a block in fetal erythropoiesis at the proerythroblast stage.

  • Rcor1 represses expression of HSCs and myeloid genes during erythropoiesis, including Csf2rb, which is important in myeloid function.

Abstract

The corepressor Rcor1 has been linked biochemically to hematopoiesis, but its function in vivo remains unknown. We show that mice deleted for Rcor1 are profoundly anemic and die in late gestation. Definitive erythroid cells from mutant mice arrest at the transition from proerythroblast to basophilic erythroblast. Remarkably, Rcor1 null erythroid progenitors cultured in vitro form myeloid colonies instead of erythroid colonies. The mutant proerythroblasts also aberrantly express genes of the myeloid lineage as well as genes typical of hematopoietic stem cells (HSCs) and/or progenitor cells. The colony-stimulating factor 2 receptor β subunit (Csf2rb), which codes for a receptor implicated in myeloid cytokine signaling, is a direct target for both Rcor1 and the transcription repressor Gfi1b in erythroid cells. In the absence of Rcor1, the Csf2rb gene is highly induced, and Rcor1−/− progenitors exhibit CSF2-dependent phospho-Stat5 hypersensitivity. Blocking this pathway can partially reduce myeloid colony formation by Rcor1-deficient erythroid progenitors. Thus, Rcor1 promotes erythropoiesis by repressing HSC and/or progenitor genes, as well as the genes and signaling pathways that lead to myeloid cell fate.

  • Submitted November 18, 2013.
  • Accepted March 12, 2014.
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