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Kordowich S.,Max Planck Institute for Biophysical Chemistry | Serup P.,Hagedorn Research Institute | Serup P.,The Danish Stem Cell Center DanStem | Collombat P.,French Institute of Health and Medical Research | And 3 more authors.
Transgenic Research | Year: 2012

Pax4 belongs to the paired-box family of transcription factors. The analysis of loss- and gain-of-function mutant animals revealed that this factor plays a crucial role in the endocrine pancreas. Indeed, Pax4 is required for the genesis of insulin-producing beta-cells. Remarkably, the sole misexpression of Pax4 in glucagon-expressing cells is able to induce their regeneration, endow these with beta-cell features, and thereby counter chemically induced diabetes. However, the function of Pax4 in adult endocrine cells remains unclear. Herein, we report the generation of Pax4 conditional knockout mice that will allow the analysis of Pax4 function in mature beta-cells, as well as in the adult central nervous system. © 2012 The Author(s).

Rasmussen K.D.,The BRIC | Rasmussen K.D.,Copenhagen University | Jia G.,The BRIC | Jia G.,Copenhagen University | And 21 more authors.
Genes and Development | Year: 2015

DNAmethylation is tightly regulated throughout mammalian development, and alteredDNAmethylation patterns are a general hallmark of cancer. The methylcytosine dioxygenase TET2 is frequently mutated in haematological disorders, including acute myeloid leukemia (AML), and has been suggested to protect CG dinucleotide (CpG) islands and promoters from aberrant DNA methylation. In this study, we present a novel Tet2-dependent leukemia mouse model that closely recapitulates gene expression profiles and hallmarks of human AML1-ETO-induced AML. Using this model, we showthat the primary effect of Tet2 loss in preleukemic hematopoietic cells is progressive and widespread DNA hypermethylation affecting up to 25% of active enhancer elements. In contrast, CpG island and promoter methylation does not change in a Tet2-dependent manner but increases relative to population doublings. We confirmed this specific enhancer hypermethylation phenotype in human AML patients with TET2 mutations. Analysis of immediate gene expression changes reveals rapid deregulation of a large number of genes implicated in tumorigenesis, including many down-regulated tumor suppressor genes. Hence, we propose that TET2 prevents leukemic transformation by protecting enhancers from aberrant DNA methylation and that it is the combined silencing of several tumor suppressor genes in TET2 mutated hematopoietic cells that contributes to increased stem cell proliferation and leukemogenesis. © 2015 Rasmussen et al

Riising E.M.,Copenhagen University | Riising E.M.,CR UK London Research Institute | Comet I.,Copenhagen University | Leblanc B.,Copenhagen University | And 6 more authors.
Molecular Cell | Year: 2014

Polycomb group (PcG) proteins are required for normal differentiation and development and are frequently deregulated in cancer. PcG proteins are involved in gene silencing; however, their role in initiation and maintenance of transcriptional repression is not well defined. Here, we show that knockout of the Polycomb repressive complex 2 (PRC2) does not lead to significant gene expression changes in mouse embryonic stem cells (mESCs) and that it is dispensable for initiating silencing of target genes during differentiation. Transcriptional inhibition in mESCs is sufficient to induce genome-wide ectopic PRC2 recruitment to endogenous PcG target genes found in other tissues. PRC2 binding analysis shows that it is restricted to nucleosome-free CpG islands (CGIs) of untranscribed genes. Our results show that it is the transcriptional state that governs PRC2 binding, and we propose that it binds by default to nontranscribed CGI genes to maintain their silenced state and to protect cell identity. © 2014 Elsevier Inc.

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