Concomitant heterochromatinisation and down-regulation of gene expression unveils epigenetic silencing of RELB in an aggressive subset of chronic lymphocytic leukemia in males. - Archive ouverte HAL Access content directly
Journal Articles BMC Medical Genomics Year : 2010

Concomitant heterochromatinisation and down-regulation of gene expression unveils epigenetic silencing of RELB in an aggressive subset of chronic lymphocytic leukemia in males.

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Jean-Brice Marteau
  • Function : Author
  • PersonId : 913268
Odile Rigaud
  • Function : Author
  • PersonId : 913269
Thibaut Brugat
  • Function : Author
  • PersonId : 913270
Nathalie Gault
  • Function : Author
  • PersonId : 913271
Laurent Vallat
  • Function : Author
  • PersonId : 913272
Mogens Kruhoffer
  • Function : Author
  • PersonId : 913273
Torben Orntoft
  • Function : Author
  • PersonId : 913274
Florence Nguyen-Khac
  • Function : Author
  • PersonId : 913275
Hélène Merle-Beral
  • Function : Author
  • PersonId : 913277

Abstract

BACKGROUND: The sensitivity of chronic lymphocytic leukemia (CLL) cells to current treatments, both in vitro and in vivo, relies on their ability to activate apoptotic death. CLL cells resistant to DNA damage-induced apoptosis display deregulation of a specific set of genes. METHODS: Microarray hybridization (Human GeneChip, Affymetrix), immunofluorescent in situ labeling coupled with video-microscopy recording/analyses, chromatin-immunoprecipitation (ChIP), polymerase chain reactions (PCR), real-time quantitative PCR (RT-QPCR) and bisulfite genome sequencing were the main methods applied. Statistical analyses were performed by applying GCRMA and SAM analysis (microarray data) and Student's t-test or Mann & Whitney's U-test. RESULTS: Herein we show that, remarkably, in a resistant male CLL cells the vast majority of genes were down-regulated compared with sensitive cells, whereas this was not the case in cells derived from females. This gene down-regulation was found to be associated with an overall gain of heterochromatin as evidenced by immunofluorescent labeling of heterochromatin protein 1α (HP-1), trimethylated histone 3 lysine 9 (3metH3K9), and 5-methylcytidine (5metC). Notably, 17 genes were found to be commonly deregulated in resistant male and female cell samples. Among these, RELB was identified as a discriminatory candidate gene repressed in the male and upregulated in the female resistant cells. CONCLUSION: The molecular defects in the silencing of RELB involve an increase in H3K9- but not CpG-island methylation in the promoter regions. Increase in acetyl-H3 in resistant female but not male CLL samples as well as a decrease of total cellular level of RelB after an inhibition of histone deacetylase (HDAC) by trichostatin A (TSA), further emphasize the role of epigenetic modifications which could discriminate two CLL subsets. Together, these results highlighted the epigenetic RELB silencing as a new marker of the progressive disease in males.
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Dates and versions

inserm-00638094 , version 1 (03-11-2011)

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Jean-Brice Marteau, Odile Rigaud, Thibaut Brugat, Nathalie Gault, Laurent Vallat, et al.. Concomitant heterochromatinisation and down-regulation of gene expression unveils epigenetic silencing of RELB in an aggressive subset of chronic lymphocytic leukemia in males.. BMC Medical Genomics, 2010, 3 (1), pp.53. ⟨10.1186/1755-8794-3-53⟩. ⟨inserm-00638094⟩
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