PRDM6, ein neuer Regulator der Kardiomyozyten-Differenzierung?
Zusammenfassung der Projektergebnisse
Transcriptional repression is an important aspect of the transcriptional control of a eukaryotic cell. Transcriptional repressors are often epigenetic key players, influencing the cellular memory in development and diseae. Most importantly, some of these molecules can be pharmacologically inhibited, and this inhibition provides clinical benefit in a wide variety of disease states, paving the way for “transcriptional therapies”. The work funded here focuses on the analysis of 5 crucial transcriptional repressors, namely PRDM6/PRISM and the HDAC family members HDAC1, HDAC2, HDAC3, HDAC8 and HDAC9. We could show that PRDM6/PRISM is a pivotal factor in controlling the proliferative gene program in smooth muscle cells. We elucidated the negative feedback loop controlling HDAC9 transcription and provided evidence for its role in the muscle differentiation circuitry. We then moved on to generate knockout models for all four class I histone deacetylases. We analysed the cardiac deletion of HDAC1, HDAC2 and HDAC3. Current and ongoing work is focusing on characterising the HDAC8 knockout, and analysing the influence of different HDAC isoforms in disease, mainly obesity and cancer.
Projektbezogene Publikationen (Auswahl)
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PRISM/PRDM6, a transcriptional repressor that promotes the proliferative gene program in smooth muscle cells. Mol Cell Biol. 2006 Apr;26(7):2626-36
Davis CA, Haberland M, Arnold MA, Sutherland LB, McDonald OG, Richardson JA, Childs G, Harris S, Owens GK, Olson EN
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Histone deacetylases 1 and 2 redundantly regulate cardiac morphogenesis, growth, and contractility. Genes Dev. 2007 Jul 15;21(14):1790-802
Montgomery RL, Davis CA, Potthoff MJ, Haberland M, Fielitz J, Qi X, Hill JA, Richardson JA, Olson EN
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Regulation of HDAC9 gene expression by MEF2 establishes a negative-feedback loop in the transcriptional circuitry of muscle differentiation. Mol Cell Biol. 2007 Jan;27(2):518-25
Haberland M, Arnold MA, McAnally J, Phan D, Kim Y, Olson EN
