Clin Res Cardiol 98, Suppl 1, April 2009

V57 - The impact of histone modifications on gene expression and transcription factor activity in mouse cardiomyocytes
J. J. Fischer1, M. Schueler1, M. Tönjes1, J. Schlesinger1, A. Brodarac1, S. Sperling1
1Vertebrate Genomics/Cardiovascular Genetics, Max-Planck-Institut für Molekulare Genetik, Berlin;
The high impact of histone acetylation on transcription and on the phenotype is well characterized; e.g., class II histone deacetylases control cardiac growth and gene expression in response to stress stimuli. We present a genome-wide profile of activating histone modification marks such as histone 3 and 4 acetylation, and histone 3 K4 mono/di/trimethylation in the contracting mouse cardiomyocytes cell line Hl-1 and exemplarily in P1.5 mouse right ventricle. Moreover, the co-occurrence and functional consequence of these histone modifications with binding sites of Nkx2.5, Gata4, Mef2a and Srf was investigated.
Using chromatin-immunoprecipitation and array detection analysis we obtained 2.500-3.000 genomic sites characterized by at least one of the studied histone modification and 500-1.500 transcription factor binding sites, respectively. Approximately two-third of histone modifications as well as transcription factor bindings co-occur at close distance, which points to a high co-regulator activity. Consequently the functional consequence of this co-occurrence was studied using gene expression information obtained in wild-type and siRNA treated cells by expression arrays. These data show that all histone modifications as well as transcription factors mainly act as activators of transcription when present singly. However, in contrast to Nkx2.5, Gata4 as well as Srf only show their full transcriptional activation capacity if they co-occur with histone 3 acetylation marks. This indicates that acetylation of histone 3, probably via p300, supports the activating function of Gata4 and Srf.
Taken together, these data demonstrate the interplay between epigenetic marks and transcription factors in controlling gene transcription and point to the necessity of considering both with equal importance. The application of histone deacetylation inhibitors is currently being tested in preclinical trials and it will be of high importance to gain our understanding of the role of histone modifications in normal and diseased hearts.