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home > cellbio > labore > celldifflab > index.html.de

Research area

The interplay between cell proliferation and differentiation controls not only development but also regeneration. Therefore its regulatory mechanisms are of interest, also as possible therapeutic targets. Based on our studies, we predict that the transcriptional co-repressor TPA-inducible sequence 7 (TIS7) is one of the players affecting cellular regeneration events. TIS7, induced by the mitogen TPA or growth factors, is differentially expressed in various polarized cell types. We have shown that TIS7 interacts with the SIN3 complex and represses transcription in an HDAC-dependent manner. In the TIS7-regulated downstream target genes we have identified a common regulatory motif C/EBPalpha-Sp1 transcription factor "module". Furthermore, TIS7 has the ability to inhibit the Wnt signaling in an HDAC-dependent manner. TIS7 expression increases during the process of tissue regeneration following a challenge like muscle crush damage or intestinal resection. Our previous studies have shown that in TIS7 knockout mice the expression of myogenic regulatory proteins is deregulated and the differentiation and fusion potential of muscle satellite cells is impaired.

Muscle satellite cells grown under differentiation conditions. Immunofluorescence microscopy images depict: MF20 - differentiated myoblasts marker protein (red), pICln - TIS7-interacting methylosome subunit protein (green), and DAPI (blue)

Fused TIS7 wt skeletal muscle cells grown under differentiation conditi-ons in culture. Raster electron scanning micrograph

Lack of fat vacuoles in the jejunum of TIS7 SKMc15 double knockout mice (right). Oil red oil staining; magnification 40x.

Left: TIS7 SKMc15 double knockout mice are significantly leaner. 6 months old male mice; n= 6. Chow diet. Right: TIS7 SKMc15 double knockout mice gain significantly less weight upon feeding with high fat diet. 11 weeks male mice; n= 11; 3 weeks high fat diet.

Major achievements

The group of our collaborators around Prof. Chris Karp at the Cincinnati College of Medicine, USA, using our TIS7 knockout mice as a specific experimental animal model, identified TIS7 to be the main modifier of the severity of the lung disease in cystic fibrosis. This lung disease is the major cause of morbidity and mortality in cystic fibrosis, an autosomal recessive disease caused by mutations in CFTR. In cystic fibrosis, chronic infection and dysregulated neutrophilic inflammation lead to progressive airway destruction. Neutrophils, but not macrophages, from TIS7-deficient mice showed blunted effector function. In vivo, TIS7 deficiency caused delayed bacterial clearance from the airway, but also less inflammation and disease. In humans, TIS7 polymorphisms were significantly associated with variation in neutrophil effector function. These data indicated that TIS7 modulates the pathogenesis of cystic fibrosis lung disease through the regulation of neutrophil effector function. These findings were published as a mutual collaboration in the journal Nature. A second member of a novel gene family, SKMc15, is a protein which shares with TIS7 high homology at the amino acid level. Therefore, our laboratory generated SKMc15 single as well as TIS7 SKMc15 double knockout mice and now concentrates on the identification of the functional role of both genes and their protein products. Interestingly, the TIS7 SKMc15 double knockout mice have a prominent phenotype: they are significantly smaller and leaner and, most importantly, they are resistant against weight gain upon feeding with the high fat-diet. We are currently searching for the mechanism responsible for this phenotype on the molecular level.

Future goals

• Identification of molecular mechanisms responsible for the smaller body size and the lack of body fat deposits in TIS7 SKMc15 double knockout mice. The long term goal of this project is to be able to design strategies for intervention with possible signaling pathways.
• Identification of TIS7-interacting proteins and analyses of their biological role. In this project we will concentrate on further characterization of interactions between TIS7 protein complex components, mainly on their in vivo interactions within the living cell. The main focus will be on regulatory mechanisms by which TIS7 modulates gene expression of muscle-specific genes during myogenesis.
• For possible clinical application of the knowledge gained in cell culture experiments and knockout mice we will analyze the expression of both proteins, TIS7 and SKMc15 in human patients’ samples. The expression of both proteins will be detected in muscle samples freshly obtained after contusion and also following the wound healing, in order to compare their expression in intact and injured tissues. The final goal of this project is improvement of differentiation and thereby regeneration of tissues following an injury.

List of Publications