title: Genome-wide mapping of histone H3K9me2 in acute myeloid leukemia reveals large chromosomal domains associated with massive gene silencing and sites of genome instability.
abstract: A facultative heterochromatin mark, histone H3 lysine 9 dimethylation (H3K9me2), which is mediated by histone methyltransferases G9a/GLP (EHMT2/1), undergoes dramatic rearrangements during myeloid cell differentiation as observed by chromatin imaging. To determine whether these structural transitions also involve genomic repositioning of H3K9me2, we used ChIP-sequencing to map genome-wide topography of H3K9me2 in normal human granulocytes, normal CD34+ hematopoietic progenitors, primary myeloblasts from acute myeloid leukemia (AML) patients, and a model leukemia cell line K562. We observe that H3K9me2 naturally repositions from the previously designated "repressed" chromatin state in hematopoietic progenitors to predominant association with heterochromatin regions in granulocytes. In contrast, AML cells accumulate H3K9me2 on previously undefined large (> 100 Kb) genomic blocks that are enriched with AML-specific single nucleotide variants, sites of chromosomal translocations, and genes downregulated in AML. Specifically, the AML-specific H3K9me2 blocks are enriched with genes regulated by the proto-oncogene ERG that promotes stem cell characteristics. The AML-enriched H3K9me2 blocks (in contrast to the heterochromatin-associated H3K9me2 blocks enriched in granulocytes) are reduced by pharmacological inhibition of the histone methyltransferase G9a/GLP in K562 cells concomitantly with transcriptional activation of ERG and ETS1 oncogenes. Our data suggest that G9a/GLP mediate formation of transient H3K9me2 blocks that are preserved in AML myeloblasts and may lead to an increased rate of AML-specific mutagenesis and chromosomal translocations.
authors.affiliation: Division of Biostatistics and Bioinformatics and Penn State Institute for Personalized Medicine, Hershey, Pennsylvania, United States of America.
authors.forename: Anna C
authors.initials: AC
authors.lastname: Salzberg
authors.affiliation: Penn State College of Medicine, Dept. Biochemistry & Molecular Biology, H171, Hershey, Pennsylvania, United States of America.
authors.forename: Abigail
authors.initials: A
authors.lastname: Harris-Becker
authors.affiliation: Penn State College of Medicine, Department of Neural and Behavioral Sciences, Hershey, Pennsylvania, United States of America.
authors.forename: Evgenya Y
authors.initials: EY
authors.lastname: Popova
authors.affiliation: Penn State Cancer Institute; Milton S. Hershey Medical Center, 500 University Drive, Hershey, Pennsylvania, United States of America.
authors.forename: Nikki
authors.initials: N
authors.lastname: Keasey
authors.affiliation: University of Virginia Cancer Center, Charlottesville, Virginia, United States of America.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Loughran
authors.affiliation: Penn State Cancer Institute; Milton S. Hershey Medical Center, 500 University Drive, Hershey, Pennsylvania, United States of America.
authors.forename: David F
authors.initials: DF
authors.lastname: Claxton
authors.affiliation: Penn State College of Medicine, Dept. Biochemistry & Molecular Biology, H171, Hershey, Pennsylvania, United States of America.
authors.forename: Sergei A
authors.identifier: http://orcid.org/0000-0003-1890-1862
authors.initials: SA
authors.lastname: Grigoryev
mesh_terms: D002454:Cell Differentiation; D002874:Chromosome Mapping; D020868:Gene Silencing; D042822:Genomic Instability; D006657:Histones / Q000235:genetics*; D006801:Humans; D020014:K562 Cells; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D000090063:Proto-Oncogene Mas; D014158:Transcription, Genetic
chemical_list: D006657:Histones; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas