A promoter DNA demethylation landscape of human hematopoietic differentiation

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.

[1]  Frank Lyko,et al.  Genome-wide promoter DNA methylation dynamics of human hematopoietic progenitor cells during differentiation and aging. , 2011, Blood.

[2]  P. Real,et al.  Nodal/Activin signaling predicts human pluripotent stem cell lines prone to differentiate toward the hematopoietic lineage. , 2010, Molecular therapy : the journal of the American Society of Gene Therapy.

[3]  Michael Weber,et al.  Targets and dynamics of promoter DNA methylation during early mouse development , 2010, Nature Genetics.

[4]  P. Menéndez,et al.  iPSC lines that do not silence the expression of the ectopic reprogramming factors may display enhanced propensity to genomic instability , 2010, Cell Research.

[5]  Pablo Menendez,et al.  Human Induced Pluripotent Stem Cells Develop Teratoma More Efficiently and Faster Than Human Embryonic Stem Cells Regardless the Site of Injection , 2010, Stem cells.

[6]  Michael A McDevitt,et al.  Acute myeloid leukemia is characterized by Wnt pathway inhibitor promoter hypermethylation , 2010, Leukemia & lymphoma.

[7]  Irving L. Weissman,et al.  A comprehensive methylome map of lineage commitment from hematopoietic progenitors , 2010, Nature.

[8]  G. Crawford,et al.  Modular utilization of distal cis-regulatory elements controls Ifng gene expression in T cells activated by distinct stimuli. , 2010, Immunity.

[9]  Martin J. Aryee,et al.  Epigenetic memory in induced pluripotent stem cells , 2010, Nature.

[10]  L. Schwarzfischer,et al.  Active DNA demethylation in human postmitotic cells correlates with activating histone modifications, but not transcription levels , 2010, Genome Biology.

[11]  J. Lieberman,et al.  Small RNAs Guide Hematopoietic Cell Differentiation and Function , 2010, The Journal of Immunology.

[12]  P. Menéndez,et al.  The ROCK Inhibitor Y-27632 Negatively Affects the Expansion/Survival of Both Fresh and Cryopreserved Cord Blood-Derived CD34+ Hematopoietic Progenitor Cells , 2010, Stem Cell Reviews and Reports.

[13]  M. Kimmel,et al.  Conflict of interest statement. None declared. , 2010 .

[14]  Peter A. Jones,et al.  Epigenetics in cancer. , 2010, Carcinogenesis.

[15]  G. Melen,et al.  Bone marrow mesenchymal stem cells from infants with MLL-AF4+ acute leukemia harbor and express the MLL-AF4 fusion gene , 2009, The Journal of experimental medicine.

[16]  Jon W. Huss,et al.  BioGPS: an extensible and customizable portal for querying and organizing gene annotation resources , 2009, Genome Biology.

[17]  R. Jaenisch,et al.  DNA methylation protects hematopoietic stem cell multipotency from myeloerythroid restriction , 2009, Nature Genetics.

[18]  M. Fraga.  Genetic and epigenetic regulation of aging. , 2009, Current opinion in immunology.

[19]  J. Cigudosa,et al.  Genetic stability of human embryonic stem cells: A first-step toward the development of potential hESC-based systems for modeling childhood leukemia. , 2009, Leukemia research.

[20]  Pablo Martínez-Camblor,et al.  Non-parametric k-sample tests: Density functions vs distribution functions , 2009, Comput. Stat. Data Anal..

[21]  G. Melen,et al.  Feeder-free maintenance of hESCs in mesenchymal stem cell-conditioned media: distinct requirements for TGF-β and IGF-II , 2009, Cell Research.

[22]  R. Spang,et al.  New insights into the biology and origin of mature aggressive B-cell lymphomas by combined epigenomic, genomic, and transcriptional profiling. , 2009, Blood.

[23]  V. Tishkov,et al.  D-Amino acid oxidase: Physiological role and applications , 2008, Biochemistry (Moscow).

[24]  M. Fraga,et al.  Cancer Genes Hypermethylated in Human Embryonic Stem Cells , 2008, PloS one.

[25]  T. Mikkelsen,et al.  Dissecting direct reprogramming through integrative genomic analysis , 2008, Nature.

[26]  A. Órfão,et al.  NG2 antigen is expressed in CD34+ HPCs and plasmacytoid dendritic cell precursors: is NG2 expression in leukemia dependent on the target cell where leukemogenesis is triggered? , 2008, Leukemia.

[27]  T. Mikkelsen,et al.  Genome-scale DNA methylation maps of pluripotent and differentiated cells , 2008, Nature.

[28]  Matteo Pellegrini,et al.  Promoter CpG methylation contributes to ES cell gene regulation in parallel with Oct4/Nanog, PcG complex, and histone H3 K4/K27 trimethylation. , 2008, Cell stem cell.

[29]  Brad T. Sherman,et al.  Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources , 2008, Nature Protocols.

[30]  T. Mikkelsen,et al.  Genome-wide maps of chromatin state in pluripotent and lineage-committed cells , 2007, Nature.

[31]  S. Yagi,et al.  Epigenetic regulation of Nanog gene in embryonic stem and trophoblast stem cells , 2007, Genes to cells : devoted to molecular & cellular mechanisms.

[32]  Edgar Schmitt,et al.  Epigenetic Control of the foxp3 Locus in Regulatory T Cells , 2007, PLoS biology.

[33]  Sergey W. Popov,et al.  Epigenetic processes play a major role in B-cell-specific gene silencing in classical Hodgkin lymphoma. , 2006, Blood.

[34]  V. Diehl,et al.  Patterned CpG methylation of silenced B cell gene promoters in classical Hodgkin lymphoma-derived and primary effusion lymphoma cell lines. , 2005, Journal of molecular biology.

[35]  N. Komatsu,et al.  Thrombopoietin initiates demethylation-based transcription of GP6 during megakaryocyte differentiation. , 2004, Blood.

[36]  D. Littman,et al.  Functional and Molecular Analysis of the Double-Positive Stage-Specific CD8 Enhancer E8III during Thymocyte Development , 2005 .

[37]  Harumi Saito,et al.  RTP Family Members Induce Functional Expression of Mammalian Odorant Receptors , 2004, Cell.

[38]  Satoshi Tanaka,et al.  Epigenetic Control of Mouse Oct-4 Gene Expression in Embryonic Stem Cells and Trophoblast Stem Cells* , 2004, Journal of Biological Chemistry.

[39]  M. Busslinger.  Transcriptional control of early B cell development. , 2004, Annual review of immunology.

[40]  J. Miguel,et al.  Quantitative analysis of bcl-2 expression in normal and leukemic human B-cell differentiation , 2004, Leukemia.

[41]  Brad T. Sherman,et al.  DAVID: Database for Annotation, Visualization, and Integrated Discovery , 2003, Genome Biology.

[42]  F. Prósper,et al.  The composition of leukapheresis products impacts on the hematopoietic recovery after autologous transplantation independently of the mobilization regimen , 2002, Transfusion.

[43]  Jiang Zhu,et al.  Hematopoietic cytokines, transcription factors and lineage commitment , 2002, Oncogene.

[44]  A. Fisher,et al.  Chromatin structure and gene regulation in the immune system. , 2002, Annual review of immunology.

[45]  Alex E. Lash,et al.  Gene Expression Omnibus: NCBI gene expression and hybridization array data repository , 2002, Nucleic Acids Res..

[46]  Paul Young,et al.  Obscurin, a giant sarcomeric Rho guanine nucleotide exchange factor protein involved in sarcomere assembly , 2001, The Journal of cell biology.

[47]  J. Kere,et al.  Myotilin, a novel sarcomeric protein with two Ig-like domains, is encoded by a candidate gene for limb-girdle muscular dystrophy. , 1999, Human molecular genetics.

[48]  R. Parwaresch,et al.  Cell lineage specificity in G-CSF receptor gene methylation , 1999, Leukemia.

[49]  A. Órfão,et al.  Comparison between a lyse-and-then-wash method and a lyse-non-wash technique for the enumeration of CD34+ hematopoietic progenitor cells. , 1998, Cytometry.

[50]  J. Nagle,et al.  Myelin transcription factor 1 (Myt1) of the oligodendrocyte lineage, along with a closely related CCHC zinc finger, is expressed in developing neurons in the mammalian central nervous system , 1997, Journal of neuroscience research.

[51]  L. Benatti,et al.  Cloning and recombinant expression of rat and human kynureninase , 1997, FEBS letters.

[52]  A. Sundan,et al.  Survival and complications in patients with thalassemia major treated with transfusion and deferoxamine , 1995 .

[53]  J. Kehrl.  Hematopoietic lineage commitment: Role of transcription factors , 1995, Stem cells.

[54]  P. Linsley,et al.  The role of the CD28 receptor during T cell responses to antigen. , 1993, Annual review of immunology.

[55]  H. Radzun,et al.  Lineage-specific methylation of the c-fms gene in blood cells and macrophages. , 1992, Leukemia.

[56]  R. Renkawitz,et al.  The involvement of demethylation in the myeloid-specific function of the mouse M lysozyme gene downstream enhancer. , 1992, Nucleic acids research.

[57]  M. Lübbert,et al.  Changes of DNA methylation and chromatin structure in the human myeloperoxidase gene during myeloid differentiation. , 1991, Blood.

[58]  F. Herrmann,et al.  Expression and regulation of myeloid-specific genes in normal and leukemic myeloid cells. , 1991, Blood.

[59]  P. Lu,et al.  Structure and function of human perforin , 1988, Nature.

[60]  I. Stamenkovic,et al.  CD19, the earliest differentiation antigen of the B cell lineage, bears three extracellular immunoglobulin-like domains and an Epstein-Barr virus-related cytoplasmic tail , 1988, The Journal of experimental medicine.

[61]  T. Enver,et al.  Role for DNA replication in beta-globin gene activation , 1988, Molecular and cellular biology.

[62]  D. Christophe,et al.  Methylation and expression of the human thyroglobulin gene. , 1986, Biochemical and biophysical research communications.

[63]  V. L. Wilson,et al.  DNA methylation and regulation of the human beta-globin-like genes in mouse erythroleukemia cells containing human chromosome 11. , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[64]  S. Weissman,et al.  Structure and nucleotide sequence of the heavy chain gene of HLA-DR. , 1983, Proceedings of the National Academy of Sciences of the United States of America.