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Positive histone marks are associated with active transcription from a methylated ICSBP/IRF8 gene
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
2008 (English)In: Gene, ISSN 0378-1119, Vol. 410, no 2, 259-267 p.Article in journal (Refereed) Published
Abstract [en]

Epigenetic modifications are critical for regulating many different aspects of normal cell biology and tumourigenesis. Gene expression may be epigenetically silenced by DNA-methylation and histone modifications, resulting in remodelling of chromatin into a repressed state. We performed DNA-methylation analysis of the ICSBP/IRF8 gene, a member of the IRF family of transcriptional regulators expressed in monocytic and lymphocytic cells, in human monoblastic U-937 cells. We found complete methylation of all 39 CpG positions located in a 308 bp sequence encompassing the proximal promoter and transcriptional start site of the ICSBP/IRF8 gene. However, strikingly, the ICSBP/IRF8 gene is still expressed. Chromatin Immuno-precipitation (ChIP) showed that RNA-Polymerase II was present at the major transcriptional start site. Investigating the histone modifications across the ICSBP/IRF8 gene we found the positive historic marks H3K9ac and H3K4me3 to be enriched at the promoter, whereas the level of H3K9me3 was low. This suggests that an active chromatin structure, indicated by histone H3 modifications and enrichment for RNA Pol II, can over-ride the silencing effect of DNA-methylation at the promoter, thereby permitting transcription of the ICSBP/ IRF8 gene.

Place, publisher, year, edition, pages
2008. Vol. 410, no 2, 259-267 p.
Keyword [en]
epigenetic, promoter, chromatin, acetylation, U-937, U-266
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-97436DOI: 10.1016/j.gene.2007.12.013ISI: 000254788900006OAI: oai:DiVA.org:uu-97436DiVA: diva2:172388
Available from: 2008-08-29 Created: 2008-08-29 Last updated: 2009-11-11Bibliographically approved
In thesis
1. Epigenetic Regulation of Gene Transcription in Hematopoietic Tumors
Open this publication in new window or tab >>Epigenetic Regulation of Gene Transcription in Hematopoietic Tumors
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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 of p21WAF1/CIP1 (CDKN1A) and p27KIP1 (CDKN1B).

TNFα alone did not induce expression of RA-induced genes analysed in Paper IV. However, ATRA in combination with TNFα showed enhanced activation of RA-induced genes. TNFα triggers demethylation of H3K9me3/H3K9me2 and H3K4me3 at RAR/RXR target genes, which were not accompanied by changes in the level of H3K9-ac. This decrease in H3 methylation by TNFα may pave way for the later ATRA-induced gene transcription.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2008. 53 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 368
Medical sciences, IRF family, ICSBP/IRF8, epigenetics, ATRA, TNFα, histone modifications, methylation, transcription, MEDICIN OCH VÅRD
urn:nbn:se:uu:diva-9206 (URN)978-91-554-7257-3 (ISBN)
Public defence
2008-09-19, Rudbeck Hall, Rudbeck Laboratory, Dag Hammarskjölds väg. 20 Uppsala, 13:15
Available from: 2008-08-29 Created: 2008-08-29Bibliographically approved

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