title: Human lymphoid translocation fragile zones are hypomethylated and have accessible chromatin.
abstract: Chromosomal translocations are a hallmark of hematopoietic malignancies. CG motifs within translocation fragile zones (typically 20 to 600 bp in size) are prone to chromosomal translocation in lymphomas. Here we demonstrate that the CG motifs in human translocation fragile zones are hypomethylated relative to the adjacent DNA. Using a methyltransferase footprinting assay on isolated nuclei (in vitro), we find that the chromatin at these fragile zones is accessible. We also examined in vivo accessibility using cellular expression of a prokaryotic methylase. Based on this assay, which measures accessibility over a much longer time interval than is possible with in vitro methods, these fragile zones were found to be more accessible than the adjacent DNA. Because DNA within the fragile zones can be methylated by both cellular and exogenous methyltransferases, the fragile zones are predominantly in a duplex DNA conformation. These observations permit more-refined models for why these zones are 100- to 1,000-fold more prone to undergo chromosomal translocation than the adjacent regions.
authors.affiliation: USC Norris Comprehensive Cancer Ctr., Los Angeles, California, USA.
authors.forename: Zhengfei
authors.initials: Z
authors.lastname: Lu
authors.affiliation: USC Norris Comprehensive Cancer Ctr., Los Angeles, California, USA lieber@usc.edu hsieh_c@med.usc.edu.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Lieber
authors.affiliation: USC Norris Comprehensive Cancer Ctr., Los Angeles, California, USA.
authors.forename: Albert G
authors.initials: AG
authors.lastname: Tsai
authors.affiliation: Department of Biochemistry & Molecular Biology, University of Florida College of Medicine, Gainesville, Florida, USA.
authors.forename: Carolina E
authors.initials: CE
authors.lastname: Pardo
authors.affiliation: Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Markus
authors.initials: M
authors.lastname: Müschen
authors.affiliation: Department of Biochemistry & Molecular Biology, University of Florida College of Medicine, Gainesville, Florida, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Kladde
authors.affiliation: USC Norris Comprehensive Cancer Ctr., Los Angeles, California, USA lieber@usc.edu hsieh_c@med.usc.edu.
authors.forename: Chih-Lin
authors.initials: CL
authors.lastname: Hsieh
mesh_terms: D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002843:Chromatin / Q000235:genetics; D043283:Chromosome Fragile Sites; D004247:DNA / Q000235:genetics; D019175:DNA Methylation; D006801:Humans; D008223:Lymphoma / Q000235:genetics*; D014178:Translocation, Genetic
chemical_list: D002843:Chromatin; D004247:DNA