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TNFα induces a reduction of histone 3 lysine 9 trimethylation and dimethylation (H3K9me2 and H3K9me2) at all-trans retinoic acid target genes
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
Manuscript (Other academic)
URN: urn:nbn:se:uu:diva-97439OAI: oai:DiVA.org:uu-97439DiVA: diva2:172391
Available from: 2008-08-29 Created: 2008-08-29 Last updated: 2010-01-13Bibliographically 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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