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

Analysis of the DNA methylome and transcriptome in granulopoiesis reveal timed changes and dynamic enhancer methylation

  1. Michelle Rönnerblad1,
  2. Robin Andersson2,
  3. Tor Olofsson3,
  4. Iyadh Douagi4,
  5. Mohsen Karimi4,
  6. Sören Lehmann4,
  7. Ilka Hoof2,
  8. Michiel de Hoon5,
  9. Masayoshi Itoh5,
  10. Sayaka Nagao-Sato6,
  11. Hideya Kawaji5,
  12. Timo Lassmann5,
  13. Piero Carninci5,
  14. Yoshihide Hayashizaki7,
  15. Alistair R. R. Forrest5,
  16. Albin Sandelin2,
  17. Karl Ekwall1,
  18. Erik Arner5, and
  19. Andreas Lennartsson1,*
  1. 1 Department of Biosciences and Nutrition, Center for Biosciences, NOVUM, Karolinska Institutet, Stockholm, Sweden;
  2. 2 The Bioinformatics Centre, Department of Biology and Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark;
  3. 3 Department of Haematology and Transfusion Medicine, BioMedical Centre, Lund University, Lund, Sweden;
  4. 4 Center for Hematology and Regenerative Medicine (HERM), Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden;
  5. 5 RIKEN Center for Life Science Technologies, Division of Genomic Technologies, Yokohama, Kanagawa, Japan;
  6. 6 RIKEN Omics Science Center, Yokohama, Kanagawa, Japan;
  7. 7 RIKEN Preventive Medicine and Diagnosis Innovation Program, Wako, Saitama, Japan
  1. * Corresponding author; email: andreas.lennartsson{at}

Key points

  • In granulopoiesis, changes in DNA methylation preferably occur at points of lineage restriction in low CpG areas.

  • DNA methylation is dynamic in enhancer elements and appears to regulate the expression of key transcription factors and neutrophil genes.


In development, epigenetic mechanisms such as DNA methylation have been suggested to provide a cellular memory to maintain multipotency but also stabilize cell fate decisions and direct lineage restriction. In this study, we set out to characterize changes in DNA methylation and gene expression during granulopoiesis using 4 distinct cell populations ranging from the oligopotent common myeloid progenitor stage to terminally differentiated neutrophils. We observed that differentially methylated sites (DMSs) generally show decreased methylation during granulopoiesis. Methylation appears to change at specific differentiation stages and overlap with changes in transcription and activity of key hematopoietic transcription factors. DMSs were preferentially located in areas distal to CpG islands and shores. Also, DMSs were overrepresented in enhancer elements and enriched in enhancers that become active during differentiation. Overall, this study depicts in detail the epigenetic and transcriptional changes that occur during granulopoiesis and supports the role of DNA methylation as a regulatory mechanism in blood cell differentiation.

  • Submitted February 4, 2013.
  • Accepted October 15, 2013.