Epigenetic modifications were shown to play an essential role in tumorigenesis. Epigenetic mechanisms can alter transcription in several ways, through DNA methylation and/or through histone modification. DNA methylation at the TSS (transcriptional start site) has been implicated in tumor development and gene silencing. However, several examples of atypical methylation were shown. In Paper I we present the ICSBP/IRF8 gene that belongs to the IRF family and has characteristics of a tumor suppressor gene. The ICSBP/IRF8 is fully methylated in the promoter and TSS regions in U-937 and despite high expression of the gene. Presence of positive histone marks suggests that methylated DNA can be overridden by histone modification.
In Paper II a panel of 13 MM (multiple myeloma) cell lines and 9 primary patient tumors were analysed for methylation status of the ICSBP/IRF8 gene. In most cell lines (8/13) the gene was partially or fully methylated and partial methylation was also observed in 1/9 primary tumors. In vitro methylation analysis and treatment with 5-aza-2’deoxycytidine (DAC) proved that the ICSBP/IRF8 gene is silenced by methylation and may be associated with the malignant phenotype.
In Paper III and IV the NFκB signalling pathway was analysed and the role of ATRA and TNFα induction. In Paper III the data shows that activation of the NFκB pathway is essential in ATRA-induced terminal differentiation in the U-937 cell line and IκBα (S32A/S36A) inhibits ATRA-induced differentiation and G1 cell cycle arrest. This was accompanied by delayed down-regulation of several cyclins (A and E) and up-regulation…
Contents
Introduction
DNA methylation
DNA methyltransferase
Methyl CpG-binding proteins
Chromatin modifications
Nucleosome remodelling
Histone modifications
Histone methyltransferases
Histone demethylases
Histone acetyltransferases and deacetylases
Histone variants
Epigenetic regulation of transcription
The IRF family
The ICSBP/IRF8 and IRF4 genes
Hematopoietic tumors
Leukemia
Multiple Myeloma
Acute Promyelocytic Leukemia (APL)
NFB signalling
Present investigation
Aims
Paper I: “Positive histone marks are associated with active
transcription from a methylated ICSBP/IRF8 gene”
Paper II: ”Epigenetic silencing of the interferon regulatory factor
ICSBP/IRF8 in human multiple myeloma.”
Paper III: ”Activation of NFB in all-trans retinoic acid induced
differentiation, cell cycle arrest and p21 (CDKN1A/Waf1) expression
in U-937 cells.”
Paper IV: “TNF induces a reduction of histone 3 lysine 9
trimethylation and dimethylation (H3K9me3 and H3K9me2) at all-
trans retinoic acid target genes.”
Acknowledgments
References
Author: Tshuikina Wiklander, Marina
Source: Uppsala University Library
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