Aberrant expression of the sox2 gene in malignant gliomas

Abstract Malignant gliomas represent over 70% of primary brain tumors and the most deadly is glioblastoma (GBM, WHO grade IV), due to frequent dysfunctions of tumor suppressors or/and oncogenes. Recent whole genome studies of gliomas demonstrated that besides genetic alterations, epigenetic dysfunctions contribute to tumor development and progression. Alterations in genes encoding epigenetic enzyme/protein or aberrations in epigenetic modification pattern have been found in gliomas of lower grade, yet no epigenetic driver was identified in GBM. We sought to identify different mechanisms driving aberrant expression of epigenetic genes in GBM. We analyzed gene expression and coding/non-coding regions of 96 major epigenetic enzymes and chromatin modifiers in 28 GBMs, 23 benign gliomas (juvenile pilocytic astrocytomas, JPAs, WHO grade I) and 7 normal brain samples. We found a profound and global down-regulation of expression of most tested epigenetic enzymes and modifiers in GBMs when compared to normal brains and JPAs. For some genes changes in mRNA level correlated with newly identified single nucleotide variants within non-coding regulatory regions. To find a common denominator responsible for the coordinated down-regulation of expression of epigenetic enzymes/modifiers, we employed PWMEnrich tool for DNA motif scanning and enrichment analysis. Among others, we discovered the presence of high affinity motifs for the E2F1/E2F4 transcription factors, within the promoters of the epigenetic enzyme/modifier encoding genes. Knockdown of the E2F1/E2F4 expression affected the expression of a set of epigenetic enzymes/modifiers. Altogether, our results reveal a novel epigenetic-related pathway by which E2F1/E2F4 factors contribute to glioma pathogenesis and indicate novel targets for glioma therapy. Supported by a National Science Centre grant 2013/09/B/NZ3/01402 (MM).

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Electron microscopy analysis of degenerating pancreatic ß cells in transgenic mice expressing the MHC Class I antigen Dd

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100160297 ◽

1990 ◽

Vol 48 (3) ◽

pp. 548-549

Author(s):

T. A. Stewart ◽

D. Liggitt ◽

S. Pitts ◽

L. Martin ◽

M. Siegel ◽

...

Keyword(s):

Type I Diabetes ◽

Disease Process ◽

Class Ii ◽

Class I ◽

Type I ◽

Aberrant Expression ◽

Mhc Molecules ◽

Endogenous Insulin ◽

Class Ii Mhc ◽

Ifn Γ

Insulin-dependant (Type I) diabetes mellitus (IDDM) is a metabolic disorder resulting from the lack of endogenous insulin secretion. The disease is thought to result from the autoimmune mediated destruction of the insulin producing ß cells within the islets of Langerhans. The disease process is probably triggered by environmental agents, e.g. virus or chemical toxins on a background of genetic susceptibility associated with particular alleles within the major histocompatiblity complex (MHC). The relation between IDDM and the MHC locus has been reinforced by the demonstration of both class I and class II MHC proteins on the surface of ß cells from newly diagnosed patients as well as mounting evidence that IDDM has an autoimmune pathogenesis. In 1984, a series of observations were used to advance a hypothesis, in which it was suggested that aberrant expression of class II MHC molecules, perhaps induced by gamma-interferon (IFN γ) could present self antigens and initiate an autoimmune disease. We have tested some aspects of this model and demonstrated that expression of IFN γ by pancreatic ß cells can initiate an inflammatory destruction of both the islets and pancreas and does lead to IDDM.

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