title: Cancer-specific changes in DNA methylation reveal aberrant silencing and activation of enhancers in leukemia.
abstract: Acute myeloid leukemia (AML) is characterized by an impaired differentiation process leading to an accumulation of immature blasts in the blood. One feature of cytogenetically normal AML is alterations to the DNA methylome. We analyzed 57 AML patients with normal karyotype by using Illumina's 450k array and showed that aberrant DNA methylation is significantly altered at enhancer regions and that the methylation levels at specific enhancers predict overall survival of AML patients. The majority of sites that become differentially methylated in AML occur in regulatory elements of the human genome. Hypermethylation associates with enhancer silencing. In addition, chromatin immunoprecipitation sequencing analyses showed that a subset of hypomethylated sites correlate with enhancer activation, indicated by increased H3K27 acetylation. DNA hypomethylation is therefore not sufficient for enhancer activation. Some sites of hypomethylation occur at weak/poised enhancers marked with H3K4 monomethylation in hematopoietic progenitor cells. Other hypomethylated regions occur at sites inactive in progenitors and reflect the de novo acquisition of AML-specific enhancers. Altered enhancer dynamics are reflected in the gene expression of enhancer target genes, including genes involved in oncogenesis and blood cell development. This study demonstrates that histone variants and different histone modifications interact with aberrant DNA methylation and cause perturbed enhancer activity in cytogenetically normal AML that contributes to a leukemic transcriptome.
authors.affiliation: Center for Hematology and Regenerative Medicine, Department of Medicine Huddinge, and.
authors.forename: Ying
authors.initials: Y
authors.lastname: Qu
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Lee
authors.initials: L
authors.lastname: Siggens
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Lina
authors.initials: L
authors.lastname: Cordeddu
authors.affiliation: Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany.
authors.forename: Verena I
authors.initials: VI
authors.lastname: Gaidzik
authors.affiliation: Laboratory for Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Kasper
authors.initials: K
authors.lastname: Karlsson
authors.affiliation: Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Bullinger
authors.affiliation: Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany.
authors.forename: Konstanze
authors.initials: K
authors.lastname: Döhner
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Karl
authors.initials: K
authors.lastname: Ekwall
authors.affiliation: Center for Hematology and Regenerative Medicine, Department of Medicine Huddinge, and.|Hematology Centre, Karolinska University Hospital, Stockholm, Sweden; and.|Hematology Unit, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Sören
authors.initials: S
authors.lastname: Lehmann
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Andreas
authors.initials: A
authors.lastname: Lennartsson
mesh_terms: D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D019175:DNA Methylation; D004742:Enhancer Elements, Genetic; D015973:Gene Expression Regulation, Leukemic; D042421:Histone Code; D006657:Histones / Q000235:genetics; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology; D011401:Promoter Regions, Genetic; D059467:Transcriptome
chemical_list: D006657:Histones