title: Comparison of DNA methylation profiles in human fetal and adult red blood cell progenitors.
abstract: BACKGROUND
  DNA methylation is an epigenetic modification that plays an important role during mammalian development. Around birth in humans, the main site of red blood cell production moves from the fetal liver to the bone marrow. DNA methylation changes at the β-globin locus and a switch from fetal to adult hemoglobin production characterize this transition. Understanding this globin switch may improve the treatment of patients with sickle cell disease and β-thalassemia, two of the most common Mendelian diseases in the world. The goal of our study was to describe and compare the genome-wide patterns of DNA methylation in fetal and adult human erythroblasts.
  
  
  METHODS
  We used the Illumina HumanMethylation 450 k BeadChip to measure DNA methylation at 402,819 CpGs in ex vivo-differentiated erythroblasts from 12 fetal liver and 12 bone marrow CD34+ donors.
  
  
  RESULTS
  We identified 5,937 differentially methylated CpGs that overlap with erythroid enhancers and binding sites for erythropoiesis-related transcription factors. Combining this information with genome-wide association study results, we show that erythroid enhancers define particularly promising genomic regions to identify new genetic variants associated with fetal hemoglobin (HbF) levels in humans. Many differentially methylated CpGs are located near genes with unanticipated roles in red blood cell differentiation and proliferation. For some of these new candidate genes, we confirm the correlation between DNA methylation and gene expression levels in red blood cell progenitors. We also provide evidence that DNA methylation and genetic variation at the β-globin locus independently control globin gene expression in adult erythroblasts.
  
  
  CONCLUSIONS
  Our DNA methylome maps confirm the widespread dynamic changes in DNA methylation that occur during human erythropoiesis. These changes tend to happen near erythroid enhancers, further highlighting their importance in erythroid regulation and HbF production. Finally, DNA methylation may act independently of the transcription factor BCL11A to repress fetal hemoglobin production. This provides cues on strategies to more efficiently re-activate HbF production in sickle cell disease and β-thalassemia patients.
authors.affiliation: Montreal Heart Institute, 5000 Bélanger Street, Montréal, Québec H1T 1C8 Canada ; Faculté de Médecine, Université de Montréal, 2900 Boul. Édouard-Montpetit, Montréal, Québec H3T 1J4 Canada.
authors.forename: Samuel
authors.initials: S
authors.lastname: Lessard
authors.affiliation: Montreal Heart Institute, 5000 Bélanger Street, Montréal, Québec H1T 1C8 Canada.
authors.forename: Mélissa
authors.initials: M
authors.lastname: Beaudoin
authors.affiliation: Hôpital Maisonneuve-Rosemont, 5415 Boul. de l'Assomption, Montréal, Québec H1T 2M4 Canada.
authors.forename: Karim
authors.initials: K
authors.lastname: Benkirane
authors.affiliation: Montreal Heart Institute, 5000 Bélanger Street, Montréal, Québec H1T 1C8 Canada ; Faculté de Médecine, Université de Montréal, 2900 Boul. Édouard-Montpetit, Montréal, Québec H3T 1J4 Canada.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Lettre