@article{HeisigWeberEnglbergeretal.2012,
  author    = {Heisig, Julia and Weber, David and Englberger, Eva and Winkler, Anja and Kneitz, Susanne and Sung, Wing-Kin and Wolf, Elmar and Eilers, Martin and Wei, Chia-Lin and Gessler, Manfred},
  title     = {Target Gene Analysis by Microarrays and Chromatin Immunoprecipitation Identifies HEY Proteins as Highly Redundant bHLH Repressors},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-75341},
  year      = {2012},
  abstract  = {HEY bHLH transcription factors have been shown to regulate multiple key steps in cardiovascular development. They can be induced by activated NOTCH receptors, but other upstream stimuli mediated by TGFß and BMP receptors may elicit a similar response. While the basic and helix-loop-helix domains exhibit strong similarity, large parts of the proteins are still unique and may serve divergent functions. The striking overlap of cardiac defects in HEY2 and combined HEY1/HEYL knockout mice suggested that all three HEY genes fulfill overlapping function in target cells. We therefore sought to identify target genes for HEY proteins by microarray expression and ChIPseq analyses in HEK293 cells, cardiomyocytes, and murine hearts. HEY proteins were found to modulate expression of their target gene to a rather limited extent, but with striking functional interchangeability between HEY factors. Chromatin immunoprecipitation revealed a much greater number of potential binding sites that again largely overlap between HEY factors. Binding sites are clustered in the proximal promoter region especially of transcriptional regulators or developmental control genes. Multiple lines of evidence suggest that HEY proteins primarily act as direct transcriptional repressors, while gene activation seems to be due to secondary or indirect effects. Mutagenesis of putative DNA binding residues supports the notion of direct DNA binding. While class B E-box sequences (CACGYG) clearly represent preferred target sequences, there must be additional and more loosely defined modes of DNA binding since many of the target promoters that are efficiently bound by HEY proteins do not contain an Ebox motif. These data clearly establish the three HEY bHLH factors as highly redundant transcriptional repressors in vitro and in vivo, which explains the combinatorial action observed in different tissues with overlapping expression.},
  subject      = {Biologie},
  language  = {en}
}
@article{BeckStegnerLorochetal.2021,
  author    = {Beck, Sarah and Stegner, David and Loroch, Stefan and Baig, Ayesha A. and G{\"o}b, Vanessa and Schumbutzki, Cornelia and Eilers, Eva and Sickmann, Albert and May, Frauke and Nolte, Marc W. and Panousis, Con and Nieswandt, Bernhard},
  title     = {Generation of a humanized FXII knock-in mouse-A powerful model system to test novel anti-thrombotic agents},
  series = {Journal of Thrombosis and Haemostasis},
  volume    = {19},
  journal   = {Journal of Thrombosis and Haemostasis},
  number    = {11},
  doi       = {10.1111/jth.15488},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-259567},
  pages     = {2835-2840},
  year      = {2021},
  abstract  = {Background Effective inhibition of thrombosis without generating bleeding risks is a major challenge in medicine. Accumulating evidence suggests that this can be achieved by inhibition of coagulation factor XII (FXII), as either its knock-out or inhibition in animal models efficiently reduced thrombosis without affecting normal hemostasis. Based on these findings, highly specific inhibitors for human FXII(a) are under development. However, currently, in vivo studies on their efficacy and safety are impeded by the lack of an optimized animal model expressing the specific target, that is, human FXII. Objective The primary objective of this study is to develop and functionally characterize a humanized FXII mouse model. Methods A humanized FXII mouse model was generated by replacing the murine with the human F12 gene (genetic knock-in) and tested it in in vitro coagulation assays and in in vivo thrombosis models. Results These hF12\(^{KI}\) mice were indistinguishable from wild-type mice in all tested assays of coagulation and platelet function in vitro and in vivo, except for reduced expression levels of hFXII compared to human plasma. Targeting FXII by the anti-human FXIIa antibody 3F7 increased activated partial thromboplastin time dose-dependently and protected hF12\(^{KI}\) mice in an arterial thrombosis model without affecting bleeding times. Conclusion These data establish the newly generated hF12\(^{KI}\) mouse as a powerful and unique model system for in vivo studies on anti-FXII(a) biologics, supporting the development of efficient and safe human FXII(a) inhibitors.},
  language  = {en}
}