title: A promoter DNA demethylation landscape of human hematopoietic differentiation.
abstract: Global mechanisms defining the gene expression programs specific for hematopoiesis are still not fully understood. Here, we show that promoter DNA demethylation is associated with the activation of hematopoietic-specific genes. Using genome-wide promoter methylation arrays, we identified 694 hematopoietic-specific genes repressed by promoter DNA methylation in human embryonic stem cells and whose loss of methylation in hematopoietic can be associated with gene expression. The association between promoter methylation and gene expression was studied for many hematopoietic-specific genes including CD45, CD34, CD28, CD19, the T cell receptor (TCR), the MHC class II gene HLA-DR, perforin 1 and the phosphoinositide 3-kinase (PI3K) and results indicated that DNA demethylation was not always sufficient for gene activation. Promoter demethylation occurred either early during embryonic development or later on during hematopoietic differentiation. Analysis of the genome-wide promoter methylation status of induced pluripotent stem cells (iPSCs) generated from somatic CD34(+) HSPCs and differentiated derivatives from CD34(+) HSPCs confirmed the role of DNA methylation in regulating the expression of genes of the hemato-immune system, and indicated that promoter methylation of these genes may be associated to stemness. Together, these data suggest that promoter DNA demethylation might play a role in the tissue/cell-specific genome-wide gene regulation within the hematopoietic compartment.
authors.affiliation: Department of Immunology and Oncology, Centro Nacional de Biotecnologia (CNB-CSIC), Darwin 3, Cantoblanco, Madrid E-28049, Spain.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Calvanese
authors.forename: Agustín F
authors.initials: AF
authors.lastname: Fernández
authors.forename: Rocío G
authors.initials: RG
authors.lastname: Urdinguio
authors.forename: Beatriz
authors.initials: B
authors.lastname: Suárez-Alvarez
authors.forename: Cristina
authors.initials: C
authors.lastname: Mangas
authors.forename: Vicente
authors.initials: V
authors.lastname: Pérez-García
authors.forename: Clara
authors.initials: C
authors.lastname: Bueno
authors.forename: Rosa
authors.initials: R
authors.lastname: Montes
authors.forename: Verónica
authors.initials: V
authors.lastname: Ramos-Mejía
authors.forename: Pablo
authors.initials: P
authors.lastname: Martínez-Camblor
authors.forename: Cecilia
authors.initials: C
authors.lastname: Ferrero
authors.forename: Yassen
authors.initials: Y
authors.lastname: Assenov
authors.forename: Christoph
authors.initials: C
authors.lastname: Bock
authors.forename: Pablo
authors.initials: P
authors.lastname: Menendez
authors.forename: Ana Clara
authors.initials: AC
authors.lastname: Carrera
authors.forename: Carlos
authors.initials: C
authors.lastname: Lopez-Larrea
authors.forename: Mario F
authors.initials: MF
authors.lastname: Fraga
mesh_terms: D000818:Animals; D054337:Cell Dedifferentiation; D002460:Cell Line; D019175:DNA Methylation; D053595:Embryonic Stem Cells / Q000378:metabolism; D005786:Gene Expression Regulation; D006410:Hematopoiesis / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D007231:Infant, Newborn; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic