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- Kanduri, Meena, 1974-
(author)
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The Functional Significance and Chromatin Organisation of the Imprinting Control Regions of the H19 and Kcnq1 Genes
- 2004
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Doctoral thesis (other academic/artistic)abstract
- Genomic imprinting is a phenomenon through which a subset of genes are epigenetically marked during gemtogenisis. This mark is maintained in the soma to often manifest parent of origin-specific monoalleleic expresson patterns. Genetics evidence suggests that gene expression patterns in mprinted genes, which are frequently organised in clusters, are regulated by the imprinting control regions (ICR). This thesis is mainly focused on the mechanisms through which the ICRs control the imprinting in the cluster, containing the Kcnq1, Igf2 and H19 genes, located at the distal end of mouse chromosome 7. The H19 ICR, located in the 5' flank of the H19 gene represses paternal H19 and maternal Igf2 expression, respectively, but has no effect on Kcnq1 expression, which is controlled by another ICR located at the intron 10 of the Kcnq1 gene. This thesis demonstrates that the maternal H19 ICR allele contains several DNase I hypersensitive sites, which map to target sites for the chromatin insulator protein CTCF at the linker regions between the positioned nucleosomes. The thesis demonstrates that the H19 ICR acts as a unidirectional insulator and that this property invovles three nucleosome positioning sites facilitating interaction between the H19 ICR and CTCF. The Kcnq1 ICR function is much more complex, since it horbours both lineage-specific silencing functions and a methylation sensitive unidirectional chromatin insulator function. Importantly, the thesis demonstrates that the Kcnq1 ICR spreads DNA methylation into flanking region only when it is itself unmethylated. Both the methylation spreading and silencing functions map to the same regions. In conclusion, the thesis has unraveled and unrivalled complexity of the epigenetic control and function of short strtches of sequences. The epigenetic status of these cis elements conspires to control long-range silencing and insulation. The manner these imprinting control regions can cause havoc in expresson domains in human diseases is hence emerging.
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- Sevov, Marie, et al.
(author)
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Longitudinal study of RNA-based prognostic markers in chronic lymphocytic leukemia reveals LPL as the most stable
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Other publication (other academic/artistic)abstract
- Several genes display differential expression in prognostic subsets in chronic lymphocytic leukemia (CLL), including LPL, TCL1, ZAP70 and MCL1. CLL patients commonly have an indolent course with low stage disease and long survival, and in this study we aimed to investigate the stability of RNA-based prognostic markers in such an indolent cohort over time. mRNA expression of LPL, TCL1, ZAP70 and MCL1 was measured in sequential unsorted samples obtained from 96 CLL patients at both diagnosis and a median follow-up of seven years. LPL was the only RNA-based marker that did not demonstrate any significant changes in expression in diagnostic vs. follow-up samples. Furthermore, an 82% concordance between both time-points was observed when grouping cases based on high or low expression. LPL expression was not affected by treatment and in addition, LPL expression in follow-up samples could predict overall survival. In contrast, TCL1 expression was found to increase at follow-up, especially in cases displaying low expression at diagnosis. As TCL1 promotes cell survival this increase could possibly be of importance for progression of the disease. Both ZAP70 and MCL1 mRNA expression were found to vary significantly during the disease course. In summary, using unsorted CLL samples, we have demonstrated that LPL is superior to other RNA-based markers based on stability over time. These findings fully endorse the use of LPL analysis at any time point of the disease.
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