Allele-specific gene expression patterns in primary leukemic cells reveal regulation of gene expression by CpG site methylation

  1. Lili Milani1,
  2. Anders Lundmark1,
  3. Jessica Nordlund1,
  4. Anna Kiialainen1,
  5. Trond Flaegstad2,8,
  6. Gudmundur Jonmundsson3,8,
  7. Jukka Kanerva4,8,
  8. Kjeld Schmiegelow5,8,
  9. Kevin L. Gunderson6,
  10. Gudmar Lönnerholm7,8 and
  11. Ann-Christine Syvänen1,9
  1. 1 Molecular Medicine, Department of Medical Sciences, Uppsala University, 75185 Uppsala, Sweden;
  2. 2 Department of Pediatrics, University and University Hospital, Tromsoe, 9038 Norway;
  3. 3 Department of Pediatrics, Landspitalinn, 101 Reykjavik, Iceland;
  4. 4 Division of Hematology/Oncology and Stem Cell Transplantation, Hospital for Children and Adolescents, University of Helsinki, 00029 HUS Helsinki, Finland;
  5. 5 Pediatric Clinic II, Rigshospitalet, and the Medical Faculty, the Institute of Gynecology, Obstetrics and Pediatrics, the University of Copenhagen, Copenhagen, 2100 Denmark;
  6. 6 Illumina Inc., San Diego, California 92121, USA;
  7. 7 Department of Women's and Children's Health, University Children's Hospital, 75185 Uppsala, Sweden

Abstract

To identify genes that are regulated by cis-acting functional elements in acute lymphoblastic leukemia (ALL) we determined the allele-specific expression (ASE) levels of 2529 genes by genotyping a genome-wide panel of single nucleotide polymorphisms in RNA and DNA from bone marrow and blood samples of 197 children with ALL. Using a reproducible, quantitative genotyping method and stringent criteria for scoring ASE, we found that 16% of the analyzed genes display ASE in multiple ALL cell samples. For most of the genes, the level of ASE varied largely between the samples, from 1.4-fold overexpression of one allele to apparent monoallelic expression. For genes exhibiting ASE, 55% displayed bidirectional ASE in which overexpression of either of the two SNP alleles occurred. For bidirectional ASE we also observed overall higher levels of ASE and correlation with the methylation level of these sites. Our results demonstrate that CpG site methylation is one of the factors that regulates gene expression in ALL cells.

Footnotes

  • 8 For the Nordic Society of Pediatric Hematology and Oncology.

  • 9 Corresponding author.

    E-mail ann-christine.syvanen{at}medsci.uu.se; fax 46-18-553601.

  • [Supplemental material is available online at www.genome.org.]

  • Article published online before print. Article and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.083931.108.

    • Received July 30, 2008.
    • Accepted October 27, 2008.
  • Freely available online through the Genome Research Open Access option.

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