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- Holmgren, Claes
(författare)
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Epigenetic Regulation of the H19 Chromatin Insulator in Development and Disease
- 2003
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The coordinated regulation of gene expression must be tightly controlled for normal development to occur. In mammals, this issue is further complicated by the requirement of both the maternal and paternal genomes for normal development, reflecting the fact that a subset of genes are monoallelically expressed depending on parental inheritance, a phenomenon known as genomic imprinting. The imprinted H19 and Igf2 genes are often considered as paradigms of genomic imprinting, since their monoallelic expression patterns are coordinated via a short stretch of sequence upstream of H19, known as the imprinting control region (ICR). This region is differentially methylated, with specific CpG methylation on the paternal allele. It is shown here that the ICR harbours several maternal-specific hypersensitive sites, located in linker regions between positioned nucleosomes. Furthermore, this region functions as an orientation-dependent insulator, that binds the chromatin insulator factor CTCF. The hypothesis that the methylation status of the ICR dictates the activity of the Igf2 gene 90 kb further upstream was confirmed by the demonstration that the insulator function is lost when the ICR is CpG methylated. The ICR has previously been shown to act as a silencer when positioned in a promotor-proximal position. The cause of this silencing was shown to be distance-dependent, suggesting that the silencing features of the ICR depend on a chromatin conformation that renders adjacent sequences inaccessible to the RNA polymerase. These data issue a cautionary note with respect to the interpretation of silencer functions. In several forms of cancer, the normally silent maternal IGF2 gene is expressed, possibly as a result of loss of insulator function at the ICR. The utilisation of CTCF target-sites was analysed in different tumours, and was shown to be highly variable. Methylation analysis showed that potential loss of insulator function and gain of methylation at the maternal ICR did not always correlate with biallelic expression of IGF2. Further investigations uncovered a novel mechanism, in which the activation of the IGF2 promoter was independent of insulator function in some cancers. This thesis shows that the regulation of the imprinted state of Igf2 depends on the formation of an epigenetically regulated chromatin insulator, and that the loss of IGF2 imprinting in human cancer can be attributed to several mechanisms, including a novel mechanism that neutralises chromatin insulator function.
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| 2. |
- Ohlsson, Claes, 1970-
(författare)
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Folkets fonder? : En textvetenskaplig studie av det svenska pensionssparandets domesticering
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The social and political background for this study is the change in Sweden from a system of a collective pension scheme to a system that includes elements of individual responsibility and a higher personal involvement of Swedes in pension saving funds. This phenomenon has been conceptualized as domestication, a metaphor that serves as a unifying notion in this study. The aim is to capture the idea of controlling markets from the perspective of individual investors. Two groups of texts are studied, advertising materials from banks and information from the PPM agency, responsible for the fund- based premium pension. What role do these texts play in the domestication of pension savings in commercial funds?The investigation includes a careful analysis of the settings of the texts and an identification of text purposes. Another matter of interest is the part that textual genres and their institutional framework play in the process. The methods are qualitative close reading techniques, held together by a view of language as a communicative and social phenomenon. Domestication in- volves the construction of informal relations between senders and the con- ceived reader together with individual-focused strategies. The senders share strategies of informalisation and individualisation but genres have differenti- ating roles in the actualization of domestication strategies. Domestication stabilizes the shared discourse of the banks and the PPM agency. It is how- ever doubtful that the focus on the individual’s responsibility has helped to gain trust in a pension system partially based on commercial funds.
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